ANALOGUES OF N-ACETYLARDEEMIN, METHOD OF PREPARATION AND USES THEREOF

Abstract: The present invention provides a compound having structure (I) wherein R1, R6 and R7 are independently hydrogen, OH, NH2, SH, halogen, C1-C9 linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, etc; wherein R0 and R2 are independently hydrogen, OH, linear or branched chain alkyl, -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 or -CR3R3-CH=CHR4, wherein R3 and R4 are independently hydrogen, halogen, C1-C9 linear or branched chain alkyl, phenyl, etc; wherein R5 is hydrogen, C1-C9 linear or branched chain alkyl, phenyl, etc; an wherein R8 is hydrogen, C1-C9 linear or branched chain acyl, benzoyl, etc; with the proviso that (a) when R2 is -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 or -CR3R3-CH=CHR4, then R0 is hydrogen; (b) when R0 is -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 or -CR3R3-CH=CHR4, then R2 is OH; and (c) when (i) R0 or R2 is -CR3R3-CH=CHR4, (ii) R3 and R5 are CH3 and (iii) R4 is hydrogen, then R1, R6 and R7 are not all hydrogen. Also provided are related compounds and compositions, and methods of inhibiting the growth of multidrug resistant cells by means of MDR reversal, collateral sensitivity and quantitative synergism.

Description: ANALOGUES OF N-ACETYLARDEEMIN, METHOD OF PREPARATION AND USES THEREOF This invention was made with government support under grants HL25848, CA28824, CA18856 and HL09187 from the National Institutes of Health. Accordingly, the U.S. Government has certain rights in the invention. Background of the Invention Throughout this application, citations for various publications are provided within parentheses in the text. The disclosures of these publications are hereby incorporated in their entirety by reference into this application in order to more fully describe the state of the art to which this invention pertains. The development of resistance to cytotoxic agents is a significant problem in cancer therapy. In multiple drug resistance (MDR) , cells become cross-resistant to unrelated chemotherapeutic agents. The MDR phenotype is associated with decreased drug retention and over- expression of P-glycoprotein (Pgp) , a membrane protein which mediates drug efflux. Pgp expression and chemotherapeutic resistance has also been functionally associated in leukemias and breast cancer, ovarian cancer and neuroblastoma . Methods of overcoming multidrug resistance have primarily utilized agents which "reverse" the phenotype by increasing intracellular drug concentrations in resistant cells. The reversal agents act presumably by inhibiting ?-glycoproteιn-mediated drug efflux. However, reversal agents now m clinical trials, such as verapamil and cyclosponn A, have limited utility due to toxic effects. More active agents with fewer toxic effects are needed. MDR reversal agents include various calcium channel blockers, such as verapamil, calmodulm inhibitors, steroid hormones and nomonic detergents . The present invention provides compounds which are selectively toxic to drug-resistant cells in the absence of resistant drugs. The present invention demonstrates "synergism" and "collateral sensitivity" of MDR cells toward certain compounds related to ardeemin. Since drug concentrations needed to mediate collateral sensitivity often exceed that for MDR reversal, more efficient methods of preparation are necessary to provide adequate supplies of material. The selective cytotoxicity of these agents to MDR cells may then be exploited clinically. The present invention provides new compounds and new methods for the treatment of cancer cells, not only through MDR reversal but also through collateral sensitivity and "quantitated synergism." The new compounds include analogues of amauromme (1; Takase, S. Iwami, M.; Ando, T. ; Okamoto, M.; Yoshida, K.; Horiai H. ; Kohsaka, . ; Aoki, H. ; Imanaka, H., J. Antibiot. 1984, 3_7, 1320; Takase, S.; Kawai, Y.; Uchida, I. Tanaka, H.,- Aoki, H., Tetrahedron. 1985, 4_l, 3037 Takase, S. : Itoh, Y. : Uchida, I.; Tanaka, H. ,- Aoki, H. Tetrahedron, 1986, 4_2, 5887) , ardeemin (2; Karwowski J.P. ,- Jackson, M. ,- Rasmussen, R.R. ; Humphrey, P.Ξ. Poddig, J.B.; Kohl, W.L.; Scherr, M.H. , Kadam, S. McAlpme, J.B., J. Antibiot. , 1993, 4_6, 374; Hochlowski J.E. ; Mullally, M.M.; Spanton, S .G. ; hittern, D.N. Hill, P. ; McAlpme, J.B., J. Antibiot.. 1993, £, 380) and 5-N-acetylardeemιn (3) . All of these analogues are memcers of a burgeoning class of biologically active mdole alkaloids (including aszonalemn (Kirrura, Y. , ■ Hamasaki, T., Nakajima, H. ; Isogai, A., Tetrahedron Lett. , 1982, 23 , 225) roq efortme (Scott, P.M.; Merrien, M.-A. , Pclonsky, J , Ξxoerientia, 1976, 3_2, 140; Scott, P.M.,- Polonsky, J. ; Merrien, M.-A., J. Aαric. Food Chem. , 1979, 2_7, 201) and the flustrammes (see, for example, Carle, J S., hristophersen, C , A.m Chem. Soc .. 1979, 101 , 4012; Carle, J.S ; Christophersen, C, J. Org . Chem. , 1981, 4_ , 3440) featuring a hexahydropyrrclo [2, 3- b] mdole nucleus, substituted at the benzyl c ring junction with a 1, 1-dιmethylallyl ( "reverse-prenyl" ) group. In a complementary family of alkaloids (gypset ) , the reverse-prenyl group is found at the 2- position of the indoline. (Shinohara, C; Hasumi, K.; Takei, Y. ; Endo, A., J. Antibiot , 1994, 47, 163 ; Brevianamide, E . ; Birch, A.J.; Wright, J.J., Tetrahedron , . 1970, 26 . , 2329 ) Amauromme is a vasodilator, apparently operating through calcium antagonism. (Takase, S . ,- Iwami, M. ; Ando, T. ; Okamoto, M. ; Yoshida, K.; Hoπai, H . ; Kohsaka, M. ; Aoki, H.; Imanaka, H., J. Antibiot . , 1984, 37, 1320) Compound 3 (Figure 1) is one of the most potent known agents for reversal of multidrug resistance, as measured against KBV-1 (v blastine resistant) tumor cell lines. (Karwowski, J.P.; Jackson, M.,- Ras ussen, R.R.; Humphrey, P.E.; Poddig, J.B.; Kohl, W.L. ; Scherr, M.H.; Kadam, S.; McAlpine, J.B., J Antibiot . , 1993, 4_6, 374; Hochlowski, J.Ξ. , Mullally, M M , Spanton, S G. , Whittern, D.N. , Hill, P , McAlpme, J.B., J. Antibiot , 1993, 4_6, 380) A different method cf preparing amauromme via a thio- Claisen rearrangement has been disclosed (Takase, S. : Itoh, Y. : Uchida, I. ; Tanaka, H.; Aoki, H. , Tetrahedron. 1986, 4_2 . , 5887) , but is low-yieldmg, lacks satisfactory stereocontrol, and is not applicable to preparing 3. The present invention provides compounds, including analogues and hycπds of ardeemin, amauromme and gypsetm, and compositions thereof, whicn are useful, alone or in conjunction with anticancer drugs, as MDR reversal, collateral sensitive and quantitated synergistic agents, to treat cancer and prevent the emergence of the MDR phenotype. The invention also provides a method of preparation for N-acylardeemms, previously unavailable except by fermentation, and methods of inhibiting growth of conventional p- glycoprotein MDR and Topo II gene-mutated MDR cells using ardeemin analogues and hybrids . Summary of the Invention The present invention provides a compound having the structure : 5 wherem R. , R., and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, C^-C, linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, halophenyl, benzyl, or hydroxybenzyl ; wherein R 0 and R 2 are independently hydrogen, OH, C, - C 9 linear or branched chain alkyl, -CR 3 R 3 -CH(0) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH(OH)R„ or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydrogen, halogen, x - 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy- phenyl or benzyl; wherein R 6 is hydrogen, C x - C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl , dialkoxybenzyl, indolylmethyl , alkylmercapto, or arylmercapto; and wherein R a is hydrogen, C 1 - C 9 linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyi, alkoxy- benzoyl, benzyl or -C, linear or branched chain alkyl; with the proviso that (a) when R 2 is -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH,OH, -CR 3 R 3 -CH (OH) R < or - R 3 R 3 -CH=CHR 4 , then R 0 is hydrogen; (b) when R 0 is -CR 3 R 3 - CH(0)CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R, cr then R 2 is OH; and (c) when (i) R c cr R 2 is -CR J R 3 -CH=CHR 4 , (11) R 3 and R c are CH 3 and (mj R 4 ls hydrogen, then R , R 6 and R 7 are not all hydrogen The present invention also provides a compound having the structure : wherein R and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, C j. -C 9 linear or branched chain alkyl, alkyl¬ mercapto, alkylam o, dialkylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl, where R 0 and R 5 are independently hydrogen, OH, C 1 - C 9 linear or branched chain alkyl, -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R < or -CR 3 R 3 -CH=CHR 4 ; wherein R 6 is -CR 3 R 3 -CH (O) CH 2 , -CR,R 3 -C^ 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; where R 3 and R 4 are independently hydrogen, halogen, C,-C 9 linear or branched cham alkyl, phenyl, alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl or benzyl; wherem R s is C l - linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkyl- benzoyl, alkoxybenzoyl, benzyl or -C, linear or branched cnam alkyl; and wherem Ro is hydrogen or OH; with the proviso that (a) when R D is -CR 3 R,-CH (0) CH 2 , -CR,R 3 -CK 2 CH,, -CR 3 R 3 -CH 2 CH 2 0H, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR « , then (l) R c is H, (ii) R. is -CR 3 R 3 -CH(0)CH 2 , -CR 3 R 3 -CH 2 CH , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 and (m) R_ is OH; and (b) when R is -CR 3 R -CH (0) CH 2 , -CR R 3 -CH 2 CH 3 , -CR,R,-CH 2 CK 2 OH, -CR,R 3 -CH(0H) R 4 or -CR 3 R -CH=CHR, , then li) R, is hydrogen, (ii) R, is -CR.R.-CH (0) CH 2 , -CR R,-CH 2 CH,, - CR,R, - CH 2 CH 2 0H , - CR 3 R 3 - CH (OH ) R 4 or - CR 3 R 3 - CH = CHR 4 and ( i i i ) R s OH ; and ( d ) both R, and R 7 are not hydrogen . The present invent ion further provides a compound having t he st ructure : wherein R λ is hydrogen, OH, NH 2 , SH, halogen, C^C, linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl ,- wherein R° and R 2 are independently hydrogen, OH, C^C:, linear or branched chain alkyl, -CR 3 R 3 -CH (O) CH 2 , -CR,R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydrogen, halogen, C : -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherein R 5 is hydrogen, C : -C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl , dialkoxybenzyl, indolylmethyl, alkylmercapto, or arylmercapto; and wherem R' and R" are independen ly hydrogen, Cj-C, linear or branched chain alkyl, C,-C 9 linear or branched chain acyl, benzoyl, alkylbenzoyl , dialkyibenzoyl , alkoxybenzoyl or benzyl; with the proviso that (a) when R 2 is -CR,R 3 -CH(0) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R,-CH(OH) R 4 or -CR 3 R,-CH=CHR 4 , then R„ is hydrogen; and lb' when R : is -CR,R 3 -CH (0) CH 2 , -CR.R 3 -CH 2 CH 3 , :R R,-CH 2 CH : OH, -CR R 3 -CH(OH)R 4 or -CR 3 R 3 -CH=CHR 4 , then R- is OH The present invention provides a process for synthesizing an wherein R, , R 6 and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, C^C, linear or branched cham alkyl, alkylmercapto, alkylammo, dialkylam o, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, halophenyl, benzyl, or hydroxybenzyl; where R 3 and R 4 are independently hydrogen, halogen, C^C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherein R B is hydrogen, Ci-Co linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, mdolylmethyl , alkylmercapto, or arylmercapto, and wherein R 3 is C.-C, linear or branched cham alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; which comprises: (a) (I) reacting a compound having the structure: H wherem X is Br, Cl, F, I, mesylate, triflate, tosylate, percnlcrate, hydrogensulfate, carbonate, bicarbonate or tetrafluoroborate; and R is C j -C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, or benzyl, with an acyl halide having the structure R 0 (C=O)-Z, wherein Z is F, Cl , Br or I, or an acyl anhydride having the structure [R 0 (C=O)] 2 O, wherein R 0 is C 1. -C 5 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, or 9-fluorenemethyl, to form a dicarbamate having the structure: (ii) treating the dicarbamate formed m step (a) (i) with a suitable phenylselenide reagent to form a mixture of phenylselenide dicarbamates having the structures: wherein R 2 is phenyl, C,_ - C 9 alkylphenyl, dialkylphenyl or trialkylphenyl ; and (iii) cross-coupling the mixture of phenylselenide dicarbamates formed in step (a) (ii) with (1) an σrganostannane having the structure R 3 R 3 C=CHCHR„SnR'R' ' R' ' ' wherein R 3 and R. are independently hydrogen, halogen, C. - C linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; and where R' R' ' and R' ' ' are independently a C,-C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, or (2) a Grignard reagent having the structure Z 0 MgR 3 R 3 C-CH=CHR 4 and an organome allic catalyst having the structure NiQ 2 (PR lv 3 ) 2 where Q and Z 0 are independently F, Cl, Br or I and R 1V is linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, to form a mixture of cross- coupled dicarbamates respectively having the structure: (b) (i) hydrolyzing the mixture of cross-coupled dicarbamates formed in step (a) (iii) to form a mixture of dicarbamate acids; (ii) purifying the mixture of dicarbamate acids formed in step (b) (i) ; and (m) isolating the dicarbamate :ιd having ti structure : H OR-, OP c) coupling the dicarbamate acid with an ammo acid :ster having the structure: wherem R, is C.-C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, or benzyl; to form a peptide dicarbamate having the structure: (d ) (1) deprotectmg and lactamizing the teptide dicarbamate formed in step (c) to form a d-keto- piperazme having the structure: (ii) acylating the diketopiperazme formed m step (d) d) with a compound having the structure- wherem Y is Cl, Br, F or I, to form an N-benzoylated diketopiperazme having the structure . ( m ) cyc li z mg the compound f ormed st ep α ; i n , to form an ardeemin having the structure : and (IVJ acylating the ardeemin formed in step (d) (iii) with (A) an acyl halide having the structure R β (C=0)-Z' wherein (1) R β is hydrogen and Z' is OR where R is a linear or branch chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; or (2) wherein R 8 is C,-C 9 linear or branched cham alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, and Z' is Cl, Br, F, I, or OR where R is a C^C, linear or branch cham alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; or with (B) an acyl anhydride navmg the structure [R 0 (C=0)] 2 0, wherem Ro s hydrogen, C A -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, to form an N-acylardeem . The present invention furtr.er provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of an ardeemin effective to nibit the growth of multidrug resistant cells m combination with a pnarmaceuticaliy acceptable carrier wherem the ardeemin has the structure: wherem R,, R = and R, are independently hydrogen, OH, NH 2 , SH, halogen, C - C Q linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylam o, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R 2 is hydrogen, OH, C j -C 8 linear or branched chain alkyl, -CR 3 R 3 -CH (O) CH 2 , -CR,R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydrogen, halogen, Cj-C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherein R 5 is hydrogen, Cj-C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy- phenyl, benzyl, alkoxyoenzyl, dialkoxybenzyl, indolyl- methyl, alkylmercapto, or arylmercapto; and wherem R 8 is hydrogen, -C, linear or branched chain acyl, benzoyl, alkylbenzoyl , dialkylbenzoyl, alkoxybenzoyl, benzyl or - C 9 linear or branched chain alkyl. The present invention also provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of a compound effective to inhibit the growth cf multidrug resistant cells m combination with a phar aceutically acceptable carrier wherein the compoun d has the structure : OH wherein R, and R, are independently hydrogen, halogen, C, - C 9 linear or branched chain alkyl, alkylmercapto, alkyl- amino, dialkyla ino, alkoxy, phenyl, alkylphenyl, dialk¬ ylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; wherein R 3 is hydrogen, halogen, C l -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; and wherein R β is hydrogen, C : -C, linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenz- oyl , alkoxybenzoyl, benzyl or C^C, linear or branched chain alkyl. The present invention also provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant ceils with an amount of an amauromine effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein the amauromme has the structure: wherein R and R are independently hydrogen, OK, NH , SH, halogen, C λ - C 9 linear or branched chain alkyl, alkylmercapto, alkyla ino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R, and R 2 are independently hydrogen, OH, C^C, linear or branched chain alkyl, -CR 3 R 3 -CH(O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH(OH)R 4 or -CR 3 R 3 -CH=CHR 4 ; where R 3 and R 4 are independently hydrogen, halogen, C,-C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; and wherem R 5 and R 6 are independently hydrogen, C,-C 9 linear or branched cham alkyl, acyl, acylalkyl, phenyl, alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl, benzyl, benzoyl, alkylbenzoyl and dialkylbenzoyl . Brief Description of the Figures Figure 1 shows elaboration of tπcyclic amino acid 4 to compounds 1, 2 and 3. Figure 2 shows the synthesis of an allyltricyclic inter¬ mediate, (a) NaOH, B0C 2 0, Bu 4 NHS0 4 , CH 2 C1 2 , 85%; (b) N- PSP, pTSA, Na 2 S0 4 , CH 2 C1 2 , 78% (5:1, β -. a) ; (c) allyl-SnBu 3 , Bu,Sn 2 , TolH, hv, 95%, 5:1 S:α; (d) IN NaOH, THF/MeOH, 98%, separate isomers. Figure 3 shows the synthesis of "allyl" N-acetylardeemm. (a) cyanuric fluoride, pyr dme, CH 2 Cl_, -15°C, D-Ala- OMe.HCl, NaHCC, H : 0/CH : C1 2 , (b ) 1. TMΞI, MeCN, 0 °C; 2. NH,, MeOH, DMAP; (c) KHMDS, THF, -78 C C, (d) PBu 3 , PhH; (e) LDA, THF, -78°C to RT, AcCl, reflux. Figure 4 shows the synthesis of amauromme 1. (a) N-PSP, pTSA, Na 2 S0 4 , CH 2 C1 2 , 78% (9:1, S:α) ; (b) MeOTf, (prenyl) SnBu 3 , 2 , 6-di (t-Bu) -pyridme , CH 2 C1 2 , 60%; (c) 1 N NaOH, THF/MeOH, 98%, separate isomers; (d) TMSI (2.4 equiv) , MeCN, C°C to room temperature; (e) 11 (1.1 equiv) , 10 (1 equiv) , BOP-Cl (1.1 equiv) , Et 3 N (2.3 equiv) ; CH 2 C1 2 , 78%; (f) TMSI (4 equiv) , MeCN, 0°C to room temperature, 58%. Figure 5 shows the syntnesis of N-acetylardeemm starting from tricyclic intermediate 10. (a) cyanuric fluoride, pyridme, CH 2 C1 2 -15°C, D-Ala-OMe -HCI, NaHCO,, H 2 0/CH 2 C1 2 , 71%; tb) 1. TMSI, MeCN; 0°C, 2. NH 3 , MeOH, DMA?, 76% overall, < c > KHMDS, THF, -78 C, 80%; (d) FBu 3 , PhH, 72%; (e) LDA, THF, -78°C to RT, AcCl , reflux, 82% Figure 6 shows various analogues of N-acetylardeemm and methods of preparation thereof. (a) N-acetylardeemm epoxide (useful for attachment to a polymer support and as a suicide inhibitor) , prepared by epoxidation of N- acetylardeemm; (b) dihydro-N-acetylardeemm, prepared by hydrogenation of N-acetylardeemm; (c) hydroxy-dihydro-N- acetylardeemin, prepared by hydroboration/oxidation or by epoxidation, followed by reductive ring cleavage with lithium/ammonia; (d) aldehyde analogue of N- acetylardeemin (active site alkylator) , prepared by ozonolysis or osmolysis, followed by periodate oxidation (e) organometallic addition to N-acetylardeemin aldehyde (d) or hydride reduction thereof; (f) biotinylated N- acetylardeemin for use in affinity chromatography, prepared from polymethylene ester carba te derivative of N-acetylardeemin. Figure 7 illustrates a synthetic strategy for preparing gypsetm. Figure 8 shows the preparation of 2 , 3-disubstituted indoles 26 by addition of nucleophiles to chloroindolenines . Figure 9 shows the preparation of intermediate 32. Figure 10 shows the preparation of gypsetin and gypsetin diastereoisomers . Figure 11 shows a plot of combination index (Cl) as a function of fractional effect (F a ) for two- or three-drug combinations of diketopiperazine 14, gypsetin and vmblastine on vmblastine-resistant CCRF-CEM leukemia cells . Figure 12 shows increased intracellular accumulation of [ HjVP-16 due to administration of ardeemin, N- acetylardeemin and verapamil in CCRF-CEM leukemia cells (influx assay) ,- single drug case. Figure 13 shows a plot of combination index (Cl) as a function of fractional effect (F a ) for two-drug combmations of 5-N-Ac-ardeemιn and vmblastme or. vmolastme-resistant CCRF-CEM/VBL leukemia cells, open circle, 1:40; open square, 1:100, open triangle, 1-200, mutually exclusive case. Figure 14 shows increased intracellular accumulation of [ 3 H]VP-16 due to administration of ardeemin, N- acetylardee m and verapamil in CCRF-CEM leukemia cells (efflux assay) ; pre-loaded drug. Figure 15 shows structures for diketopiperazme analogues of N-acetylardeemm: 14{A), imide acetate diketopiperazme; 14{B), diketopiperazme, 14(C) , imide- BOC diketopiperazme; 14(D) , lπiαe diacetate diketopiperazme; 14(E), N-acetyldiketonipeiazine . Figure 16 illustrates preparative routes providing diketopiperazme analogues of N-acetyi -8 -desmethyl -ardeemin: imide acetate diketopiperazme; N-acetyl imideacetate diketopiperazme; 5N-acetyl diketopiperazme; 5N-trι- fluoroacetyl diketopiperazine ,- 5N- ti if luoroacetyl imide¬ acetate diketopiperazme; 5N-BOC ιmide-30C diketopiperazme; lmide-BOC diketopiperazme. Figure 17 shows a synthetic scheme toi the preparation of N- Acetyl - 8 -des ethyl -ardeemin . Figure 18 shows the toxicity of desmethyl - ardeemin in BDF mice. Figure 19 shows the inhibition of CCRF OEM and CC RF-CEM/VLB cells treated with combinations of v olastme and various ardeemin analogues or verapamil F igure 20 illustrates efflux kinetics i or CCRF- C EM/VBL-10C cells preloaded with trit ated vmblastme for 30 mm at 37°C Cells were washed twice at 4°C, MDR agent added at 0 mm, and incubated at 37°C. Detailed Description of the Invention As used herein, the term "linear or branched alkyl group" encompasses, but is not limited to, methyl, ethyl, propyl, isopropyl, t-butyl, sec-butyl, cyclopentyl or cyclohexyl. The alkyl group may contain one carbon atom or as many as fourteen carbon atoms, but preferably contains one carbon atom or as many as nine carbon atoms, and may be substituted by various groups, which include, but are not limited to, acyl, aryl, alkoxy, aryloxy, carboxy, hydroxy, carboxa ido or N-acylamino moieties. As used herein, the terms "alkoxycarbonyl, " "acyl, ' and "alkoxy group" encompass, but are not limited to, a similar range of alkyl groups bonded to the functional group or moiety denoted by each respective term. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , n-butoxycarbonyl , benzyloxycarbonyl , hydroxypropyloxy carbonyl, aminoethoxycarbonyl , sec- butoxycarbonyl, and cyclopentyloxycarbonyl . Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl, butyryl, and pentanoyl . Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, n-butoxy, sec-butoxy, and cyclopentyloxy. As used herein, an "aryl group" encompasses, but is not limited to, a phenyl, pyridyl, pyrryl, indolyl, naphthyl, th ophenyl or furyl group, each of which may be substituted by various groups, which include, but are not limited to, acyl, aryl, alkoxy, aryloxy, carboxy, hydroxy, carboxamido or N-acylamino moieties. Examples of aryloxy groups include, but are not limited to, a phenoxy, 2 -me hylphenoxy, 3-methylphenoxy anc 2- napnthylcxy. Examples of acyloxy groups include, b t are not limited to, acetcxy, propanoyloxy, butyryloxy, pentanoyloxy and hexanoyloxy. The present invention provides a compound having the structure : wherein R l f R 6 and R 7 are independently hydrogen, OH, NH 2 SH, halogen, C^C, linear or branched chain alkyl, alkyl¬ mercapto, alkylamino, dialkylamino, alkoxy, phenyl, alk¬ ylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, halophenyl, benzyl, or hydroxybenzyl; wherein R 0 and R 2 are independen ly hydrogen, OH, C^C, linear or branched chain alkyl, -CR 3 R 3 -CH(O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR,R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR„; wherein R 3 and R 4 are independently hydrogen, halogen, C^ - C^ linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl cr benzyl; wherein R s is hydrogen, C,_ - C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl , dialkoxybenzyl, indolylmethyl , alkylmercapto, or arylmercapto; and wherein R, is hydrogen, C_, - C, linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl , alkoxy¬ benzoyl, benzyl or C j -C, linear or branched chain alkyl; with the proviso that (a) when R 2 is -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH-CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR : R ; -CH=CHR 4 , then R 2 is hydrogen; (b) when R c is -CR 3 R 3 - CH(0)CH : , -CR 3 R 3 -CH,CK 3 , -CR 3 R 3 -CH : CH : CH, -CR 3 R 3 -CH (OH) R 4 or -CR,R-,-CH=CHR 4 , then R 2 s OH; and (c) when (i) R, or R, is -CR R,-CH = CHR , in) R and R c are CH 3 and (111) R 4 is hydrogen, then R , R. and R- are not all hydrogen. In one embodiment, the present invention provides a compound, wherem R 0 , R 1( R 3 , R 4 , R 6 and R 7 are hydrogen; wherem R 2 is -CR 3 R 3 -CH=CHR 4 ; where R 5 is CH 3 ; and wherein R 9 is - (C=0) CH 3 . In another embodiment, the present invention provides a compound having the structure : In a certain embodiment, the present invention provides a compound having the structure shown above where R 0 is hydrogen. The present invention also provides a composition comprising an amount of a compound having the generic structure shown above effective to inhibit the growth of multidrug resistant cells and a pharmaceutically acceptacle carrier In one embodiment , the present invention provides the aoove composition, further comprising a cytotoxic agent. In an additional embodiment, the present invention provides a composition, wherem the cytotoxic agent is an anticancer agent In another embodiment, the present _nventιon provides the composition, as disclosed above, wnerein tne anticancer agent s adπamycm In another emnooi en , the present invention provides the compos¬ ition, as disclosed above, where the anticancer agent is vmblastme In another embodiment, the present invention provides the composition, as disclosed above, wherem the anticancer agent is paclitaxel. In a further embodiment, the present invention provides the compos¬ ition, as disclosed above, wherein R 2 is -CR 3 R 3 -CH=CHR 4 ; wherem R i( R 4 , R„ and R 7 are hydrogen; wherein R 3 and R 5 are CH 3 ; and wherem R β is -(C=0)CH 3 In a certain embodiment, the present invention provides the composition, as disclosed aoove, wherem the eftective amount of the compound is between about 0.01 mg/κg to about 25 mg/kg of body weight In another embodiment, the present invention provides the composition, as disclosed above, wherem the effective amount is between about 0.1 mg/kg to about 10 mg/kg of body weight The present invention provides a compound having the structure • wnerem R and R, are independently hydrogen, OH, NH 2 , SH, halogen, C Λ -C. linear cr branched chain alkyl, alkyl- mercapto, alkylamino, dialkylam o, alkoxy, phenyl, al<y_pnenyi, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or cenzyl , wherem R 0 and R 5 are independently hydrogen, OH, C ! -C 9 linear or branched chain alkyl, -CR 3 R 3 -CH (O) CH,, -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH,CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 6 is -CR 3 R,-CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ,- wherein R 3 and R. are independently hydrogen, halogen, C ^ -C, Linear or branched chain alkyl, phenyl, alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl or benzyl; wherein R β is hydrogen, C] . -C 9 linear or branched chain acyl, benzoyl, alkylbenz¬ oyl, dialkylbenzoyl, alkoxybenzoyl, benzyl or -C 8 linear or branched chain alkyl; and wherein R 9 is hydrogen or OH ; with the proviso that (a) when R 0 is -CR 3 R 3 -CH(0) CH 2 , -CR 3 R,-CH 2 CH 3 , -CRjR 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR,R 1 -CH=CHR 4 , then (i) R 6 is H, [ui R. is -CR 3 R 3 -CH (O) CH : , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 and (iii) R 9 is OH; and (b) when R s is - CR 3 R 3 -CH(0)CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then (i) R 0 is hydrogen, (ii) R 6 is - CR 3 R 3 -CH(0)CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR,R 3 -CH : CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR„ and (iii) R„ is OH; and (c) both R j and R 7 are not hydrogen. In one embodiment, the present invention provides a compound having the structure : R- The present invention also provides a composition comprising an amount of the compound having the structure shown above effective to inhibit the growth of multidrug resistant cells and a pharmaceutically acceptable carπer In one embodiment, the present invention provides tne composition, as disclosed above, further comprising an amount of a cytotoxic agent. In another emoodiment, the present invention provides the ccpoΞition, as disclosed above, wherem the cytotoxic agent is an anticancer agent. In another embodiment, the present invention provides the composition, as disclosed above, wherem the anticancer agent is adriamycm. In another embodiment, the present invention provides the composition, as dislosed above, wherem the anticancer agent is vmblastme. In yet another embodiment, the present invention provides the composition, as dislosed acove, wherem the anticancer agent is paclitaxel In a certain emoodiment, the present invention provides the composition, as disclosed above, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. In another embodiment, the present invention provides the compoε- ltion, as disclosed above, wherem the effective amount of the compound is between about 0 1 mg/kg to about 10 mg/kg of body weight. The present invention also provides a compound having the structure wnerein P is nydrogen, OH, NH 2 , SH, nalogen, C -C a linear cr ranched cnair. alkyl, alkylmercapto, alkylamino, dialkylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl ; wherem R 3 and R 2 are independently hydrogen, OH, C 1 - C 9 linear or branched chain alkyl, -CR 3 R 3 -CH(0) CH 2 , -CR 3 R 3 -CH 2 CH,, -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydrogen, halogen, C.-C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherem R 5 is hydrogen, C 1 - C g linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl , dialkoxybenzyl, indolyl ethyl , alkylmercapto, or arylmercapto; and where R' and R" are independently hydrogen, C z - C linear or brancned chain alkyl, C l - C linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxy¬ benzoyl or benzyl; with the proviso that (a) when R 2 is - CR 3 R 3 -CH(0) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH(OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then R 0 is hydrogen; and (b) when R 0 is -CR 3 R 3 -CH (0) CH 2 , -CR 3 R 3 -CH 2 CH 3 , - CR 3 R 3 - CH 2 CH 2 OH , -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then R 2 is OH. In one embodiment, the present invention provides a compound having the structure : In one emoodiment, the present invention provides a composition comprising an amount of the compound having me aocve structure effective to inhibit the growth of multidrug resistant cells and a pharmaceutically acceptable carrier. In another embodiment, the present invention provides a composition, as above, furtner com¬ prising an amount of a cytotoxic agent. In an additional embodiment, the present invention provides the compos¬ ition, as above, wherein the cytotoxic agent is an anti¬ cancer agent. In a further embodiment, the present invention provides the composition, as above, wherein the anticancer agent is adriamyc . In yet another embod¬ iment, the present invention provides the composition, as above, wherein the anticancer agent is vmblastine. In another embodiment, the present invention provides the composition, as above, wherem the anticancer agent is paclitaxel . In one embodiment, the present invention provides the composition, as above, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. In another embodiment, the present invention provides the composition, as above, wherem the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight. The present invention also provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of the compound having the structure: where R x is hydrogen, OH, NH 2 , SH, halogen, C -C, linear or branched chain alkyl, alkylmercapto, al ylaπinc, α . -- alkylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl , alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl, where R c and R 2 are independently hydrogen, OH, C^C , linear or branched chain alkyl, -CR 3 R 1 -CH (0) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , wherein R 3 and R 4 are mdepenαently hydrogen, halogen, C ϊ - C linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxypnenyl or benzyl, wherein R 5 is hydrogen, C - C 9 linear or branched cham alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl, benzyl, alkoxyPenzyl , dialkoxybenzyl , dclyl- methyl, alkylmercapto, or arylmercapto, and wherein R' and R' ' are independently hydrogen, C, -C 9 linear or branched chain alkyl, C 1 -C, linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl or benzyl; with the proviso that (a) when R 2 is -CR J R J - CH(0)CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then R 0 is hydrogen; and (b) when R 0 is - CR 3 R 3 -CH(0)CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then R 2 is OH; effective to inhibit the growth of multidrug resistant cells m combination with a pharmaceutically acceptable carrier. In one embodiment, the present invention provides a method, as disclosed above, further comprising admin¬ istering an amount of a cytotoxic agent . In anotner embodiment, the present invention provides a method, as disclosed above, wnerem the cytotoxic agent is an anticancer agent. In yet another embodiment, the present invention provides a method, as disclosed above, wherem the anticancer agent is adnamycm. In another embodiment, the present invention provides a method, as disclosed above, wherem the anticancer agent is inblastine In another embodiment, the present mvention provides a method, as disclosed above, wherein the anticancer agent is paclitaxei . In a certain embodiment, the present invention provides he method, as disclosed above, wherem is -CR 3 R 3 -CH=CHR 4/ - wherein R 0 , R and R are hydrogen; and wherein R 3 is CH 3 . In another embodiment, the present invention provides the method, as disclosed above, wherein the compound has the structure : and wherem R 2 is -CR 3 R 3 -CH=CHR 4 ,- wherein R,, R,_, R 4 , R ' and R ' are hydrogen; and wherein R 3 and R s are CH 3 . In another embodiment, the present invention further provides the method, as disclosed above, wherein the effective amount of the compound s between about 0.01 mg/kg to about 25 mg/kg of body weight. In another embodiment, the present invention provides the method, as disclosed above, wherem the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight . The present invention also provides a process for synthesizing an N-acylardeem having the structure: wherem R, is hydrogen, OH, NH 2 , SH, halogen, C,-C, linear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, halophenyl, benzyl, or hydroxybenzyl ,- wherein and R 4 are independently hydrogen, halogen, C 1 - C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherem R t is hydrogen, C^C, linear or branched cham alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, mdolylmethyl , alkylmercapto, or arylmercapto; wherein R 6 and R 7 are independently hydrogen, halogen, C : -C 9 linear or branched chair, alkyl, alkylmercapto, alkylamino, diaikylammo, aikcxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; and wherem R B is hydrogen, C^-C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; which cc~t)rιses : ( a, ( i reacting a compound having the structure H wherem X is Br, Cl , F, I, mesylate, triflate, tosylate, perchlorate, hydrogensulfate, carbonate, bicarbonate or tetrafluoroborate; and R is C 1 -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, bezyl or alkcxybenzyl, with an acyl halide having the structure R,(C=0)-Z, wherein Z s F, Cl, Br or I, or an acyl annvdride having the structure [R (C=0) ] 2 0, wherein R„ is C_-C linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, or 9- fluorenemethyl , to form a dicarbamate having the structure : <2>R 0 (ii) treating the dicarbamate formed in step (a) (i) with a suitable phenylselenide reagent to form a mixture of phenylselenide dicarbamates having the structures: wherein R ; is phenyl, C : -C 9 alkylphenyl, dialkylphenyl or trialkylphenyl ; and (iii) cross-coupling the mixture of phenylselenide dicarbamates formed in step (a) (ii) with (1) an organostannane having the structure R 3 R 3 C=CHCHR 4 SnR' R' ' R' ' ' wherein R 3 and R 4 are independently hydrogen, halogen, C : - C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; and wherein R' , R' ' and R' ' ' are independently a C x -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, or (2) a Grignard reagent having the structure Z„MgR 3 R 3 C-CH=CHR 4 and an organometallic catalyst having the structure NiQ 2 (PR lv s ) 2 where Q and Z 3 are independently F, Cl, Br or I and R 1V is linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, furyl, thiophenyl or benzyl, to fcrm a mixture of cross-coupled dicarbamates respectively having the structure OR 0 CR D (p ( i hydrolyzmg the mixture of cross-coupled dicarpamates formed in step (a) (m, to form a mixture of dicarbamate acids, (u) purifying the mixture of dicarbamate acids formed in step (b) d) , and (in) isolating the dicarbamate acid having the structure : JR, rp (c) coupling the dicarbamate acid with an ammo acid ester having tne structure: R= CO q wherein R 9 is C 1 -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, or benzyl; to form a peptide dicarbamate having the structure: (d) (i) deprotecting and lactamizing the peptide dicarbamate formed in step (c) to form a diketo¬ piperazme having the structure: (ii) acylating the diketopiperazine formed in step (d) (i) with a compound having the structure: wherein Y is Cl, Br, F or I , to form an N-benzoylated diketopiperazine having the structure: (iii) cyclizing the compound formed in step (d) (ii) to form an ardeemin having the structure: »nα (iv) acylating the ardeemin formed in step (d) (iii) with (A ' - an acyl halide having the structure R 8 (C=0) -Z' wherein \ J .s hydrogen and Z' is OR where R is a linear or branch chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; or (2) wherem R is C,_-C Q linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, and Z' is Cl, Br, F, I, or OR where R is a Cj-Cg linear or branch chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl,- or with (B) an acyl anhydride having the structure [R β (C=0)] 2 0, wherem R e is hydrogen, C x -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, to form an N-acylardeemm. In one embodiment, the present invention provides the process, as disclosed above, wherem R,, R b and R 7 are hydrogen. In another embodiment, the present invention provides the process, as disclosed above, wherein R 0 is t- Bu, R and R 5 are CH 3 , and X, Y and Z are Cl . In a further embodiment, the present invention provides the process, as disclosed above, wherein R, is CH 3 . In another embodiment, the present invention provides the process, as disclosed above, wherein R 3 is CH 3 and R 4 is hydrogen. In another embodiment, the present invention provides the process, as disclosed above, where R 2 is phenyl. In yet another embodiment, the present invention provides the process, as disclosed above, wherein R' , R' ' and R' ' ' are n-Bu. Step (a) (i) is performed with an acyl halide or an acyl annydride such as (BOC) 2 0 using a base such as sodium hydroxide under various reaction conditions known m the art to effect the transformation, preferably under phase transfer conditions using water and an immiscible organic solvent such as dichloromethane and a phase transfer catalyst such as tetrabutylammonium hydrogensulfate . Step [ a ) 'ii, is effected using a suitable selenaticn reagent sucn as N-phenylselenophthalimide in the presence of an organic acid, such as p-toluenesulfonic acid, and a dehydrating agent such as sodium sulfate, in an organic solvent such as dichloromethane. Step la) (m) is performed under condition (1) using an organometallic reagent such as prenyl tributylstannane, and an alkyl triflate, such as methyl triflate, m the presence of a non- teracting base, such as 2,6-dι-tert- butylpyridine, initially at low temperatures ranging from -100°C to -50oC, but preferably at -78°C, and later at high temperatures, ranging from ambient temperatures to reflux temperature, but preferably at reflux, m an organic solvent, such as dichlorometr.ane Alternatively, step (.a) (m) may be carried out under condition (2) using a Grignard reagent with various organometallic catalysts, such as NiCl 2 (PPh 3 ) 2 . (Cf. uh, T.-Y.; Ni, Z.- J., Synthesis, 1990, 89; Okamura, H.; Miura, M. ; Kosugi, K. ; Takei, H., Tetrahedron, 1980, 2Λ , 87.) By using a Grignard reagent having the structure ZMgR wherein R is linear or branched alkyl or an aryl, the disclosed process is extended to prepare ardeemins with alkyl or aryl moieties in place of allyl moieties. Step (b) d) is effected using any of several satisfactory saponifying agents, including sodium hydroxide or potassium hydroxide, in a mixed aprotic and protic solvent system, such as THF and methanol, at high temperatures, ranging from ambient to reflux, but preferaoly at reflux. Steps (b; (ii) and (m) are accomplished by one or more metnod of chromatography known to one of skill m tne art, sucn as flash chromatography or hign pressure liquid chromatography, on a suitable adscrbant phase, including, but not limited to, spherical or irregular silica gel, reverse-phase silica gel, and aluminum oxide. Step (c) is effected using a variety of peptide coupling conditions known in the art, for example, using cyanuric fluoride in excess in the presence of an organic base such as pyridme in a non-interacting solvent such as dichloromethane, at a temperature ranging from -45°C to -5°C, but preferably at -15°C. Subsequent coupling of the preformd fluoride with a suitable amine ester m biphasic conditions, preferably including water containing a base such as sodium bicarbonate and an organic solvent sich as dichloromethane. The invention also provides a process, as above, wherein the α-carbon of the ammo acid ester has an R or S configuration Deprotectmg step (d) d) is performed using a selective electrophilic deprotectmg agent such as tπmethylsilyl iodide in a polar aprotic solvent such as acetoni rile, followed by lactamizing step (d) d) involving treatment with a mild base such as ammonia and addition of a cyclization catalyst such as DMAP, or thermolysis. Step (d) (ii) was effected using a non-nucleophilic base such as KHMDS in excess at low temperature, ranging from -100°C to -50°C, but preferably at -78°C, polar aprotic solvent such as THF Cyclizing step (d) (m) proceeds on treatment with a condensing agent such as tributylphosphme m a non- mteract g solvent such as benzene, xylenes or toluene, but preferably in benzene. Step (d) (iv) by treatment with a non-nucleophilic base sucn as lithium diisopropylamide at low temperature, ranging from -100 C to -50°C, preferaoly at -78°C, in a polar aprotic solvent such as THF, or with diisopropylamine from room temperature to reflux temperature Other useful solvents include such ethereal solvents as dioxane, diethyl ether The present invention provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of an ardeemin effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein the ardeemin has the structure : wherein R r , R 6 and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, Ci-C 9 linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherem R 0 and R 2 are independently hydrogen, OH, C,_-C 9 linear or branched chain alkyl, -CR 3 R,- CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CK 2 OH, -CR 3 R 3 -CH(OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherem R 3 and R 4 are independently hydrogen, halogen, Cj . -C<, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl or benzyl; wherein R 5 is hydrogen, C j -C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, oenzyl, alkoxybenzyl , dialkoxybenzyl , indolyl ethyl , alkylmercapto, or arylmercapto; and wherem R 3 is hydrogen, C,-C 9 linear or branched chain alkyl, C,_-C 9 linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl or benzyl. In one embodiment, the present invention provides the method, as disclosed above, further comprising admin- istermg an amount of a cytotoxic agent. in another embodiment, the present invention provides the method , as disclosed above, wherein the cytotoxic agent s an anticancer agent. In another embodiment, the present invention provides the method, as disclosed above, wherein the anticancer agent is adriamycin. In another embodiment, the present invention provides the method, as disclosed above, wherem the anticancer agent is vmblastme. In another embodiment, the present invention provides the method, as disclosed above, wherem the anticancer agent is paclitaxel. In one embodiment, the present invention provides the method, as disclosed above, wherem the ardeemin has the structure : In another embodiment, the present invention provides the method, as disclosed above, wherein the ardeemin is N- acetylardeemm. In a certain embodiment, the present invention provides the method, as described above, wherein R 2 is -CR 3 R 3 -CH=CHR 4 ; wherem R. , R 3 , R 4 , R 6 and R 7 are hydrogen; wherein R s is CH 3 ; and wherein R 8 is H. In another embodiment, the present invention provides the method, as disclosed above, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 πg/rcg of body weight. In another embodiment, the present invention provides the method, as disclosed above, wherem tne effective amount of the compound is between about 0 1 mg/kg to about 10 mg/kg of body weight The present invention further provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells w th an amount of a compound effective to inhibit the growth of multidrug resistant cells m combination with a pharmaceutically acceptable carrier wherem the compound has the structure: " P, wherem R x and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, y - 9 linear or branched chain alkyl, alkyl¬ mercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl, wnerem R„ and R 5 are independently hydrogen, OH, C,-C l ear or branched chain alkyl, -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR,R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , wherem R 6 is hydrogen, OH, C j -C, linear or branched chain alkyl, -CR 3 R 3 -CH (0) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR,R 3 -CH 2 CH ; OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , wherem R 3 and R 4 are independently hydrogen, halogen, C x -C 9 lmear or branched chain alkyl, pnenyl , alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl or benzyl, wherem R„ is hydrogen, C,-C 9 lmear or branched cnain acyl, benzoyl, alkyl¬ benzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl or C j -C, linear or brancned chain alkyl, and wherein R 9 is hydrogen or OH In one embodiment, the present invention provides the method, as disclosed above, wherem R 1 , R 7 and R β are hydrogen; and wherein R 3 is CH 3 . In one embodiment, the present invention provides the method, as disclosed above, wherein the compound has the structure : OH In another embodiment, the present invention provides the method, as disclosed above, further comprising admin¬ istering a cytotoxic agent. In another embodiment, the present invention provides the method, as disclosed above, wherein the cytotoxic agent is an anticancer agent. In a certain embodiment, the present invention provides the method, as disclosed above, wherein the anticancer agent is adπamycm. In another embodiment, the present invention provides the method, as disclosed above, where the anticancer agent is vinblastme. In yet another embodiment, the present invention provides the method, as disclosed above, wherein the anticancer agent is paclitaxel. In one embodiment, the present invention provides the method, as disclosed above, wherem R 1( R 7 and R 8 are hydrogen; and wherein R 3 is CH 3 . In a certain embodiment, the present invention provides the method, as disclosed above, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. In another embodiment, the present invention provides the method, as disclosed above, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight. The present invention also provides a method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of an amauromine effective to inhibit the growth of multidrug resistant cells combination with a pharmaceutically acceptable carrier wherem the amauromme has the structure: TT . wherein R : and R-, are independently hydrogen, OH, NH- , SH, halogen, Cj-C, lmear or branched chain alkyl, alkyl¬ mercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R, and R 2 are independ¬ ently hydrogen, OH, C x - C 9 linear or branched chain alkyl, - CR 3 R 3 - H (0) CH : , -CR 3 R 3 -CH 2 CH 3 , - CR 3 R, - CH 2 CH 2 OH , -CR,R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherem R 3 and R 4 are independently hydrogen, halogen, C,_ - C a linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl cr benzyl; and wherem R ; and R c are independently hydrogen, C,-C 9 lmear or branched chain alkyl, acyl, acylalkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl, benzyl, benzoyl, alkylbenzoyl or dialkylbenzoyl. In one embodiment, the present invention provides the method, as disclosed above, further comprising admin¬ istering a cytotoxic agent. In another embodiment, the present invention provides the method, as disclosed above, wherein the cytotoxic agent is an anticancer agent. In a certain embodiment, the present invention provides the method, as disclosed above, wherem the anticancer agent is adria ycm. In another embodiment, the present invention provides the method, as disclosed above, wherem the anticancer agent is vmblastme. In yet another embodiment, the present invention provides the method, as disclosed above, wherem the anticancer agent is paclitaxel. In a certain embodiment, the present invention provides the method, as disclosed above, wherein R 0 , R 5 , R 6 and R 7 are hydrogen. In another embodiment, the present invention provides the method, as disclosed above, wherein R x and R 2 are -CR 3 R 3 -CH=CHR 4 ; wherem R 3 is CH 3 ; and wherein R 4 is hydrogen. In one embodiment, the present invention provides the method, as disclosed above, wherem the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. In another embodiment, the present invention provides the method, as disclosed above, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight. As used herein, the term "pharmaceutically acceptable carrier" means any of the standard pharmaceutical carriers. Suitable carriers are well known in the art and may include, but are not limited to, any of the standard pnarmaceutical carriers. The compositions provided herein may be constituted into any form suitable for the mode of administration selected. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. The drug may otherwise be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile mjectiP-e medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Optimal dosages to be administered may be determined by those skilled m the art, and will vary with the particular ardeemin, gypsetin or amauromme analogue m use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, gender, diet, and time of administration Experimental Details General Procedures All air- and moisture-sensitive reactions were performed in a flame-dried apparatus under an argon atmosphere unless otherwise noted. Air-sensitive liquids and solutions were transferred via syringe or canula. Wherever possible, reactions were monitored by thm-layer chromatography (TLC) . Gross solvent removal was performed m vacuum under aspirator vacuum on a Buchi rotary evaporator, and trace solvent was removed on a high vacuum pump at 0.1-0.5 mmHg Melting points (mp) were uncorrected and performed m soft glass capillary tubes using an Electrothermal series IA9100 digital melting point apparatus. Infrared spectra (IR) were recorded using a Perkin-Elmer 1600 series Fourier-Transform instrument. Samples were prepared as neat films on NaCl plates unless otherwise noted. Absorption bands are reported n avenumber= (cm l ) . Only relevant, assignable bands are reported Proton nuclear magnetic resonance (-H NMR) spectra were determined using a Varian 200, 300 or 400 MHz spectrometer, as indicated below Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane (TMS; δ=0 ppm) using residual CHC1, as a lock reference (δ=7.25 ppm) Multiplicities are abbreviated m the usual fashion. s=smglet; d=doublet; t=trιplet, q=quartet; m=multιplet, or=broad. Carbon nuclear magnetic resonance ι u C NMR) spectra were performed on a Varian 300 spectrometer at 75 MHz with composite pulse decoupling. Samples were prepared as with H NMR spectra, and chemical shifts are reported relative to TMS (0 ppm) , residual CHCl 3 was used as an internal reference (δ=77.0 ppm) All high resolution mass spectral (HRMS) analyses were determined by Fast Atom Bombardment techniques or electron impact lonization (El) on a JEOL JMS-DX 303HF mass spectrometer with perfluorokerosene (PFK) as an internal standard. Low resolution mass spectra (MS) were determined by either electron impact lonization (El) or chemical lonization (CD using the indicated carrier gas (ammonia or methane) on a Delsi-Nermag R-10-10 mass spectrometer For gas chromatography/mass spectra f GCMS) , a C3-5 fused capillary column (30 m, C.25mm thickness) was used with helium as the carrier gas. Typical conditions used a temperature program from 60- 250°C at 40°C/mιn. Thin layer chromatography (TLC) was performed using precoated glass plates (silica gel 60, 0.25 mm thickness) Visualization was done oy illumination with a 254 nm UV lamp, or by immersion m amsaldehyde stain (9.2 mL p-anisaldehyde in 3.5 mL acetic acid, 12.5 mL cone, sulfuric acid and 338 mL 95% ethanol (EtOH) ) and heating to colorization. Flash silica gel chromatography was carried out accordmg to the standard protocol Unless otnerw se noted, all solvents and reagents were commercial grade and were used as received, except as indicated herembelow, where solvents were distilled under argon using the drying methods listed m paretneses CH 2 CI 2 (CaH 2 ) , benzene (CaH 2 ) , THF (Na/ketyl' 1 , Et 2 0 'Na/κetyD , diisopropylamme (CaH 2 ) Abbreviations Ac acetate, acetyl Bn benzyl BOC or Boc t-butyloxycarbonyl CH 2 C1 2 dichloromethane DMF N,N-dimethylforma ide DMAP 4-dimethylaminopyridine DDQ 2 , 3 -dιchloro- 5 , 6 -dιcyano- l , 4 -benzocrumone EtOAc ethyl acetate hex hexane LiHMDS lithium hexamethyldisilazide KHMDS potassium hexamethyldisilazide M DR multiple drug resistance MeCN acetonitrile OTf triflate PSP pnenylselenophthalimide r.b. round bottom flask r. t . room temperature THF tetrahydrofuran TLC thin layer chromatography Def nitions Cl combination index; CI<1, =1, and 1 indicates synergism, additivitv and antagonsims respectively, as defmed by the combination index equa ion rollateral sensitive agent compound acting alone tnat kills or inhibits the growth of drug-resistant cancer cells even more than regular wild-type cancer cells :RI dose-reduction index; signifies how much the dose of each drug m a synergistic combination may be reduced at a given effect level compared with the dose of eacn drag a one (toxicity toward one host may be avoided or reduced when the dose is reduced) median-effect dose or concentration such as ED 50 or IC S0 Fa fraction affected m slope of the median-effect plot, signifying the shape of the dose- effect curve linear correlation coefficient synergism drug combinations that yield a combination index smaller than one, and yield an isobologram that shows combination data point (s) on the lower left of the graph EXAMPLE 1 Bis (tert-butyloxycarbonyl) -L-tryptophan (7) : Powdered sodium hydroxide (80 mg, 2.0 mmol) was added to a solution of tryptophan methyl ester hydrochloride (100 mg, 0.39 mmol) and tetrabutylammonium hydrogen sulfate (14 mg, 0.04 mmol) in CH 2 Cl 2 (4 mL) , and the mixture was stirred for two hours at room temperature. Bis (t- butyloxy) carbonic anhydride (257 mg, 1.18 mmol) was then added and the mixture was stirred fcr 15 hours more, and tnen filtered through a pad of celite and evaporated m vacuo. The residue was purified by flash chromatography (30% EtOAc ihexane) to afford the title compound (150 mg, 91% yield) as a white waxy solid: R. = 0.60 (silica gel, i0% EtOAc m hexane) or -47.9 CHC1, λ H NMR (200 MHz, CDC1 δ 8.08 (d, J=6.2 Hz, IH, H-7) 7.46 (d, J=7.6 Hz, IH, K-4) , 7.37 (s, IH, H-2) , 7.30 (t, J=6.9 Hz, IH, H-6) , 7.21 (t, J=6.9 Hz, IH, H=5) , 5.10 (d, J=8.0 Hz, IH, NH) , 4.63 (dd, J=12.3, 5.5 Hz, IH, H-2') 3.67 (s, OMe) 3.24 (dd, J=14.55, 5.3 Hz, IH, H-l' 3.15 (dd, =14.2 Hz, 5.3H, IH, H-l' ) , 1.64 (s, 9H, t-butyl) ppm; 13 C NMR (75 MHz, CDC1 3 ) δ 171.6, 154.2, 148.8, 134.7, 130.0, 123.8, 123.4, 121.8, 118.1, 114.5, 82.9, 79.1, 76.5, 53.0, 51.6, 27.5 ppm; IR (film) 3388, 2977, 1731, 1502, 1453, 1369, 1255, 1159, 1086 c 1 ; MS (Cl) calc'd for C 2: H 3: N 2Cέ ; M/e 418.2104, found 418.2121; 436 (M' NH 4 ) , 419 (M + H) , 418 (M) , 363, 236; Analysis calc'd for C 22 H 30 N 206 . C, 63.14; H, 7.23; N, 6.59; found: C, 63.45; H, 7.57; N, 6.54. EXAMPLE 2 Selenide ester (8) : To a stirring suspension of 7 (7.33 g, 17.5 mmol) , N-phenylselenophthalimide (7.94g, 26.3 mmol) , and sodium sulfate (24.9 g, 175 mmol) in CH 2 C1 2 (35 mL, 0.5 M) was added p-toluenesulfonic acid (333 mg, 1.75 mmol) . The milieu was stirred for 6-8 hours, filtered through a Celite pad over cotton, and the filtered solids rinsed with CH 2 Cl 2 . The filtrate was washed with 1 N NaOH (3 times) , and the combined aqueous layers back-extracted with CH 2 C1 2 . The combined organic layers were dried over Na 2 S0 4 , filtered, concentrated and chromatographed (silica gel, 10% ethyl acetate in hexane) to yield 7.48 g (74%) of an off-white solid as a 9:1 ratio of diastereomers. R f = 0.64 (silica gel, 30% EtOAc in hexane) ; [a] 2 ° D = -41. A (c 1.0, CHClj) ; : H NMR (400MHz, CDC1 3 ) δ 7.41-7.09 (m, SH) , 7.01 (t, J=7.95 Hz, IH) , 6.25 (s, IH, H-l) , 3.88 (dd, J=9.8, 6.6 Hz, IH, H-2) , 3.63 (s, 3H, OMe) , 2.88 (dd, J=12.4, 6.7 Hz, IH, H-3) , 2.36 (dd, J=12.5, 10.0 Hz, IH, H-3) , 1.54 (s, 9H, t-butyl) , 1.42 (s, 9H, t-butyl) pp ; ;; C ΪIMR (75 MHz, CHCl 3 ) δ 172.3, 152.1, 142.0, 137.5, 132.8, 129.3, 129.2, 128.9, 124.1, 123.9, 123.5, 123.4, 123.0, 117.7, 117.6, 83.0, 82.7, 81.6, 80.9, 59.1, 52.1, 38.6, 28.3, 28.2 ppm,- IR (film) 2981, 1758, 1748, 1712, 1393, 1366, 1159 cm \- MS (Cl) calc'd for C 28 H 34 N 2C6 Se (Se80i : m/e 575.1663, found 575.1669; 573 (M) , 434 (M - SePh -r NH.) ; Analysis calc'd for C 5 H 34 N 2C6 Ξe : C, 58.64; H, 5.97; N, 44.88; found: C, 58.80; H, 6.22; N, 4.58. EXAMPLE 3 Prenyl Ester (9) : To a -78 °C solution of 8 (1.51 g, 2.63 mmol) and 2 , 6-di-tert-butylpyrid e (2.65 mL, 11.8 mmol) m CH 2 C1 ^ (26 L 0.1 M) was added methyl trifuorcmethane- sulfonate (1.34 mL, 11.8 mmol) and then prenyl tributyl- stannane (3.86 mL, 11.8 mmol) under argon. The solution was allowed to warm to room temperature over 6 hours then was attached to a condenser and refluxed for 14 hours. The solution was cooled, quenched with an equal volume of sat. NaHCO, and the organic layer was separated. The aqueous layer was extracted with CH,C1_ (2 times) . The comomed organic layers were washed w th brine, dried over Na 2 S0 4 , filtered, concentrated and chromatographed (silica gel, 10-40% EtOAc in hexane) to give 770 mg (60%) of a white foam as a 9:1 mixture of diastereomers: R f = 0.63 (silica gel, 30% EtOAc m hexane) ; [a] 0 D =-68.8° (c 1.0, CHC1 3 ) ; : H NMR (400 MHz, CDC1 3 ) 6 7.23 (d, J=8.1 Hz, IH) , 7.18 (t, J=7.5 Hz, IH) , 7.14 (d, J=6.8 Hz, IH) , 7.02 (t, J=7.6 Hz, IH) , 6.13 (s, IH, H-l) , 5.84 (dd, J=17.4, 10.8 Hz, IH) , 5.05 (d, J=10.8 Hz, IH) , 4.98 (d, J=17.4 Hz, IH) , 3.78 (dd, J=10.2, 8.6 Hz, IH, H-2) , 3.69 (s, 3H, OMe) , 2.36 (dd, J=12.3, 6.6 Hz, IH, H-3) , 2.25 (dd, J=12.4, 10.2 Hz, IH, H-3) , 1.54 (s, 9H, t-butyl) , 1.43 (s, 9H, t-outyl) , 1.00 (s, 3H, CH 3 ) , 0.92 (s, 3H, CH 3 ) ppm; -'C NMR '75 MHz, CDCl 3 ) δ 172.8, 152.1, 143.2, 142.9 133.5, 12S.4, 125.3, 124.5, 123.0, 118.0, 114.1, 81.2 81.0, 78.6, 1.3, 59.3, 51.9, 40.2, 34.8, 28.6, 28.2 22.9, 22.1 ppm; IR (film) 2977, 2800, 1750, 1704, 1599 1481, 1462, 1390, 1367, 1253, 1167, 1061, 1012, 318 cm - MS [ l' calc'd for C ;7 H 3β N 2C , • m/e 486.2730, found 486.2744; 487 (MH) , 431, 401, 387. EXAMPLE 4 Prenyl acid (10) : A solution of 9 146 τg, 0.30 mmol; was heated under reflux m THF (2.5 mL) , ethancl (2.5 L; , IN NaOH (1.5 mL) and water (1 L) for 12 hours, then the mixture was allowed to cool to room temperature. The solution was carefully acidified to pH 4 with 5% citric ac d solution. The solution was extracted with ethyl 5 acetate (4x10 mL) , the combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered, concentrated and chromatographed (silica gel, 35:60:5 ethyl acetate :hexane : acetic acid) to yield 142 mg (98%) of a white solid as a 9:1 mixture of diastereomers. 10 Repeated chromatography allows the separation of the diastereomers. : [ ] 2C D = -57.5° (c 1.0, CHC1 3 ) ; '"H NMR (400 MHz, CDC1 δ 7.37 (d, J=7.7 Hz, IH) , 7.25 (d, J=6.9 Hz, IH) , 7.14 (t, J=6.9 Hz, IK) , 7.04 (t, J=7.4 Hz, IH) , 6.14 (s, IH, H-l) , 5.84 (dd, J=17.2, 10.7 Hz, IH) , 5.07 15 (d, J=10.6 Hz, IH) , 5.00 (d, J=17.2 Hz, IH) , 3.78 (dd, J=9.9, 6.9 Hz, IH, H-2) , 2.37 (m, 2H, 2xH-3) , 1.53 (s, 9H, t-butyl) , 1.40 (s, 9H, t-butyl) , 1.01 (s, 3H, CH 3 ) , 0.92 (s, 3H, CH 3 ) ppm; 13 C NMR (75 MHz, CDC1 3 ) δ 178.4, 152.1, 143.1, 142.8, 133.3, 128.5, 128.2, 124.6, 123.2, " D 118.1, 114.3, 81.4, 81.2, 78.6, 61.7, 59.2, 40.3, 34.7, 28.3, 28.2, 22.9, 22.1 ppm; IR (film) 3500-2800, 2980, 1713, 1479, 1395, 1366, 1252, 1152, 1020 cm "1 ; MS (Cl) calc'd for C 26 H 36 N 206 : m/e 472.2573, found 472.2562; 473, 373. EXAMPLE 5 Peptide (13) : Acyl fluoride: To a -15 °C solution of 10 (1.63 g, 3.45 mmol) and pyridine (0.275 mL, 3.45 mmol) in CH : C1 : (30 mL! in a plastic test tube was added cyanuric fluoride (1.24 mL, 13.8 mmol) dropwise over a 2-3 min period. After one hour at -15 J C, the solution was quenched with ce, and extracted with CH 2 C1 2 (3 x 25 mL) . The combined extracts were dried over Na 2 S0 4 , filtered, and concentrated to give an off-white foam (1.53 g, 93%) . EXAMPLE 6 Peptide: The above acyl fluoride (1 53 g, 3.22 mmol) in CH ; C1 2 (16 mL) was added via canula to a solution of D- Ala-OMe-HCl (450 mg, 3.22 mmol) , NaHC0 3 (541 mg, 6 44 mmol) , and water (16 mL) . This biphasic solution was stirred vigorously for 45 mm, then water was added, and the solution was extracted with CH 2 C1, (3 x 20mL) . The combined organic layers were washed with brine, dried over Na 2 SO„ , filtered, concentrated, and chromatographed to yield 1.37 g (71% from 10) of a white foam: R f = 0.50 (silica gel, 50% EtOAc m hexane) , { a] 2r ~ = -73.3 > c=1.7, CHC1 ; H NMR ^ 00 MHz, CDC1 δ 7 40 ,cr s, IH, H-4) , 7.24 (t, J=8.0 Hz, IH) , 7.17 (d, J=7 2 Hz, IH) , 7.0 (t, J=7.6 Hz, IH) , 6.23 (d, J=7.2 Hz, IH, Ala-NH) , 6.15 (s, IH, H-5) , 5 87 (dd, J=17.6, 10.8 Hz, IH, H-19) , 5.08 (d, J=10.8 Hz, IH, H-20-cιs) , 5.01 (d, J=17.6 Hz, IH, H-20- trans) , 4.60 (q, J=7.2 Hz, 7.2H, H-8) , 3.74 (s, 3H, OMe) , 3.69 (dd, J=10.4, 6.8 Hz, IH, H-15b) , 2.43 (dd, J=12.8, 10.4 Hz, IH, H-16) , 2.32 (dd, J=12.8, 10.4 Hz, IH, H-16) 1.55 (s, 9H, t-Bu) , 1.39 (br s, 9H, t-Bu) , 1.38 (d, 7.2 Hz, 3H, H-17) , 1.04 (s, 3H, Me) , 0.95 (s, 3H, Me) ppm; 13 C NMR (300 MHz, CDC1 3 ) δ 173.2, 171.7, 152.3, 143.2, 142.8, 133.6, 128.5, 124.8, 123.2, 118.0, 114.3, 114 2, 81.5, 81.0, 79.2, 61 5, 61.1, 52.3, 47.7, 40.3, 35.5, 28.4, 28.2, 22.9, 22.2, 18 4 ppm; IR (film, NaCl) 3412, 3327, 3080, 2979, l^iO, 1602, 1532, 1478, 1455, 1370, 1161, 1022, 922, 736, cm "; MS calc'd for C,„H 43 N :: , : m/e 557 3101, found 557.3093. EXAMPLE 7 Diketopiperazine (14) : Peptide 13 '1.464 g, 2.63 mmol) was azeotroped twice with benzene, dissolved m freshly distillled dry MeCN (26 mL) , chilled to 0'C under argon, and treated witn TMSI (1.12 L, 7 89 mmol 1 dropwise over a 2 mm period. After 40 mm, the reaction was dumped mto sat. NaHC0 3 and extracted with CH,C1 2 (3 x 25 mL) The combined organic layers were washed with brme, dried over Na 2 S0 4 , filtered, concentrated and chromatocfraphed (60-100 % EtOAc in hexane) to give a white foam (810 mg, 86%) ; R f =0.35 (silica gel, 100% EtOAc) . To the above foam in a 0°C solution of MeOH saturated with ammonia (11.3 mL) was added DMAP (111 mg, 0.91 mmol) . The solution was stirred overnight with gradual warming to room temperature, concentrated, and chromatographed (silica gel, 60-100% EtOAc in hexane) to give a white foam (633 mg, 86%) in 74% overall yield from 13. R f = 0.30 (silica gel, 100% EtOAc) ; [a] 2 °, = -311° (c 0.09, CHC1 3 ) ; -H NMR ( 400 MHz, CDC1 3 ) δ 7.16 id, J=7.5 Hz, IH) , 7.11 (app t, J=7.5, 7.2 Hz, IH) , 6.76 (app t, J=8.1, 7.5 Hz, IH) , 6.60 (d, J=8.1 Hz, IH) , 5.95-6.60 (br ε, IH, variable, Ala-NH) , 5.97 (dd, J=17.4, 10.8 Hz, IH, H-19) , 5.56 (s, IH) , 5.12 (d, 9.8 Hz, IH, H-20-cis) , 5.08 (d, 17.6 Hz, IH, H-20-trans), 4.90-5.15 (br s, IH, 5-NH) , 4.00 (dq, J=7.2, 3.6 Hz, IH, H-8) , 3.92 (d, J=ll.l, 6.3 Hz, IH, H-15b) , 2.54 (dd, J=12.6, 6.3 Hz, IH, H-16) , 2.42 (dd, J=12.6, 11.1 Hz, IH, H-16) , 1.39 (d, J=7.2 Hz, 3H, Ala-Me) , 1.12 (s, 3H, Me) , 1.00 (s, 3H, Me) ppm; 13 C NMR (300 MHz, CDC1 3 ) 6 169.1, 166.7, 150.0, 143.5, 128.9, 128.8, 125.1, 118.8, 114.6, 109.1, 77.7, 61.3, 57.7, 53.3, 40.9, 36.8, 22.9, 22.4, 20.6 ppm; IR (film, NaCl) 3322, 3083, 2979, 2876, 1665, 1607, 1452, 1368, 1316, 1216, 1134, 1084, 922, 749, 666 cm 1 ; MS calc'd for C 19 H 23 N 302 : m/e 325.1790, found 325.1808. EXAMPLE 8 Benzoylated diketopiperazine (15) : o-Azidobenzoyl chloride: To a 0°C CH 2 Cl : solution (16 mL) of o- azidobenzoic acid (1.26 g, 7.75 mmol) and oxalyl chloride (1.35 mL, 15.5 mmol) was added cne drop of DMF. The solution was allowed to warm to room temperature for 1 hour, concentrated via a stream of argon and then m vacuo, redissolved in THF (7.75 L, l.C M) , and chilled to -78 r C. Separately, a -78°C THF solution of 14 (315 mg, 0.968 mmol) under argon was treated with KHMDS (2.52 mL, 0.5M in toluene, 1.26 mmol) dropwise over a 2 min period. The resultant green solution was stirred at -78°C for 30 min. Then 2.9 mL of the acid chloride solution prepared above was added via canula over a 3-5 mm period. After 20 min, more KHMDS (0.97 mL, 0.48 mmol) was added at -78°C, and after 5 min more acid chloride (1.0 L, 0.97 mmol) was added. The solution was allowed to warm, to room temperature, quenched with sat. NaKCO,, and extracted with EtOAc (3 times) . The combined organic layers were washed with brine, dried over Na 2 S0 4 , filtered, concentrated, and chromatographed (silica gel, 10-50% EtOAc in hexane) to give 15 as a white foam (364 mg, 80%) then 100% EtOAc to recover unreacted 14 (10-15%) . R £ = 0.55 (silica gel, 50% EtOAc in hexane; [ ] 2 - -143°(c 0.01, CHCl 3 ) ; *H NMR (300 MHz, CDC1 3 ) δ 7.49 (ddd, J=7.8, 6.2, 1.5 Hz, IH) , 7.40 (dd, J=7.8, 1.5 Hz, IH) , 7.23 (t, J=7.6, 7.5 Hz, IH) , 7.15 (m, 3H) , 6.78 (dd, J=7.5, 7.3 Hz, IH) , 6.63 (d, J=7.5 Hz, IH) , 5.98 (dd, J=17.3, 10.8 Hz, IH) , 5.62 (s, IH, N-CH-N) , 5.15 (d, J=ll.l Hz, IH) , 5.11 (d, J=17.3 Hz, IH) , 5.08 (s,lH, NH) , 5.07 (q, J=7.2 Hz, IK, Ala-CH) , 4.C5 (dd, J=9.8, 7.6 Hz, IH, Trp-CH) , 2.53 ( , 2H, Trp- CH 2 ) , 1.50 (d, J=7.2 Hz, 3H, Ala-CH,) , 1.12 (s, 3H) , 1.00 (s, 2H) ppm; 13 C NMR (300 MHz, CDCl 3 ) δ 169.0. 167.8, 166.6, 149.8, 143.2, 136.3, 131.8, 129.1, 128.5, 128.4, 125.2, 125.0, 118.9, 118.1, 114.8, 109.3, 77.5, 61.6, 59.1, 55.5, 40.9, 36.8, 22.8, 22.3, 17.7 ppm; IR (film, NaCl) 3356, 2973, 2129, 1722, 1674, 1598, 1580, 1485, 14S7, 1448, 1383, 1301, 1219, 1150, 752 cm "1 ; MS calc'd for C :s H : .N 6C3 : m/e 470.2066, found 470.2C73. EXAMPLE 9 Ardeemin (2) : Tπbutylphosphme (0.171 mL, 0.69 mmol) was added to a solution of 15 (293 mg, 0.623 mol) m dry benzene (6.2 mL) . The orange solution was stirred for 4 hours under argon, concentrated, triturated with 30% EtOAc in hexane to remove tributylphosphme oxide, and then chromatographed (silica gel, 10-50% EtOAc m hexane to recover ardeemin (191 mg, 72%) and then 100% EtOAc to recover 30 mg of 14) : R f = 0.45 (silica gel, 50% EtOAc in hexane) . EXAMPLE 10 5-N-Acetylardeemin (3) : 0.5 M LDA preparation: To a solution of disopropylamine (0.147 mL, 1.05 mmol) m THF (1.45 mL) at -78 υ C was added BuLi (0.40 mL, 2.5M in hex; 1.00 mmol) under argon. After 3 min, the solution was warmed towards room temperature for 15 mm and then recooled to -78 ϋ C. EXAMPLE 11 5-N-Acetylardeemin: Method A. A solution of ardeemin (68.0 mg, 0.159 mmol) m THF '1.6 L) at -78 C C was treated with 0.5 M LDA (0.320 L, 0.16 mmol) . The green solution was warmed towards room temperature for 5 min, recooled to -78°C, and treated with acetyl chloride (0.028 mL, 0.35 mmol) . The solution was warned tc room temperature and then warmed to reflux for 30 mm, cooled, diluted with EtOAc and quenched with sat . NaHCO, The organic phase was separated and washed with sat. NaHCO, (2 x 5 mL) and brme fl x 5 mL) , dried over Na 2 SC. , filtered, concentrated and chromatographed 'silica gel, 10-50% ethyl acetate m hexanej to give 59.7 -" ■ g '80%) of an off-white foam. Recrystall zation from hot MeOH σave granular crystals: R f = 0.38 (silica σel, 50% EtOAc in hexane) ; [ ] : c = -43° (c=0.45, CHCi 3 ) , m.p. 229-31 ' (uncorr.) , IR (film, NaCl) 3359, 2924, 2853, 1732, 1682, 1606, 1469, 1402, 1160, 756 cm * ; MS (CD calc'd for C 2β H 23 N 403 : m/e 468.2162, found 468.2147; 425 (M-Ac) , 399 (M-C S H , 356 (M- (C 5 H 9 +Ac) ) . Method B. To a solution of ardeemin (1.5 grams, 3.507 mmole) in 6 L of acetic anhydride was added 0.6 mL of N,N-dnsopropylethylamine . The reaction mixture was warmed to 60°C for 24 hours. Progress of the reaction was monitored by TLC (EtOAc :Hexane, 3:4; R £ 0.4 (acetate) , R £ 0.45 (ardeemin) ) When the reaction was completed, the mixture was cooled to room temperature, diluted witn 10 mL of chloroform and quenched by dropwise addition of sat. NaHC0 3 solution (added until all of the acetic anhydride was converted to sodium acetate) . The organic phase was separated and washed with 5% citric acid (to remove N, N-diisopropylethylamme) , dried over anhydrous sodium sulfate, filtered and concentrated. Chrom- atography (silica gel, 10 to 30% gradient, ethyl acetate in hexane) afforded 1.45 grams (88%) of product, m.p. 229.8-231.3°C, [a] 2= D =51.1. EXAMPLE 12 Allyl Ester (9(A)) : A stream cf argon was bubbled through a solution of the phenyl selenide (500 mg, 0.871 mmol, 5:1 mixture of diastereomers) , allyl tributyl- stannane (0.543 L, 1.74 mmol) and hexabutyldistannane θ.043 L, 0.087 mmol) in toluene \3.7 mL, 0.1 M) for 40 minutes. The solution was then irradiated under arσon or 9 nours using a medium pressure mercury lamp. Direct chromatograpny of the solution on silica gel (eluted with 5-30% ethyl acetate m hexane) gave 375 mg (94%) of a white foam as a 5:1 mixture of diastereomers. : R, = 0.60 130% etnvi acetate m hexane) . The conditions as outlined for 10, 13, 14, 15, and 2 were followed to give 10(A) , 13(A) , 14(A), 15(A), and 2(A) , respectively, with similar yields. : H NMR data were obtained for 10(A) , 13(A), 14(A) , and 15(A) , EXAMPLE 13 "Allyl" 5-N-acetylardeemin (3(A)) : Following Method A as outlined for 3 gave a 56% yield of a white solid. ! H NMR (400 MHz, CDC1 3 ) : δ 8.27 (d, J=8.1 Hz, IH) 8.03 (b s, IH) , 7.79 (ddd, J=8.1, 7.0, 1.1 Hz, IH) 7.72 (d, J = 8.3 Hz, IH) 7.52 (ddd, J=8,0, 7.0, 1.0 Hz, IH) 7.35 (m, 2H) 7.21 (t, J=7.5 Hz, IH) 5.93 (b S, IH) 5.58 (m, IH) 5.44 (q, J=7.2 Hz) 5.14 (d, J=17.0 Hz, IH) 5.13 (d, 10.4 Hz, IH) 4.57 (dd, J=10.7, 5.8 Hz, IH) 3.25 (dd, -1=13.2, 5.9 Hz, IH) 2.65 (s, 3H) 2.61 (m, 3H) 1.48 (d, J=7.3 Hz, 3H) ppm; HRMS calculated for C 26 H 24 N 4 0 3 : m/e 440.1848, found 440.1852; 398 (M-Ac) , 357 (M-Ac-C 3 H 5 ) . Biological Results 1. Cytotoxicity Relative cytotoxicity toward DC-3F hamster lung cells follows the ordering: IC S0 : 5-N-Ac-ardeemm (5.06 μM) < ardeemin (10.25 μM) < 5- N-Ac "Allyl" ardeemin (17.39 μM) In human leukemic CCRF-CEM cells, the relative ordering is as follows : IC,-: Ardeemin (20.8 μM) < 5-N-Ac-ardeemm (29. S μM) < 5- N-Ac "Allyl" ardeemin (53.3 μM) Ardee m derivatives are not particularly cytotoxic, and may be used as a modulator for a cytotoxic drug, or used directly against MDR cells. II Cross-Resistance DC-3F/ADII p-glycoprotem MDR cells are 3 to 11 fold collaterally more sensitive to ardeemin derivatives than those of the parent DC-3F cells Collateral sensitivity is also observed for verapamil. CCRF-CEM/VBL, 00 human leukemic p-glycoprotem MDR cells are more sensitive to ardeemin derivatives than those of the parent CCRF-CEM cells Ardeemm derivatives are similarly effective against CCRF-CEM cells, but are less effective against cells resistant to VM-26 with mutated Topo II gene (CCRF- CEM/VM-1) . III. Transport of MDR Substrate Ardeemm derivatives increase intracellular accumulation of antitumor agent VP-16 (a substrate for MDR) , in CCRF- CEM human leukemic cells, as measured by the influx of H]VP-16 during a 30 mm period at 37°C 5-N-Ac-Ardeemm (30 μM) and ardeemin (20 μM) increased VP-16 accumulation 66% and 33%, respectively. Verapamil (10*0 μM) also increased VP-16 accumulation. For MDR cells resistant to topo II n citor, ' .14-26 'CCRF/VM-l , ardeem derivatives increased intracellular accumulation of VP-16. 5-N-Ac-aroeemm (30 μM) and ardeemin (20 μM) increased VP-16 accumulation 1.95-fold and 1.51-fold, respectively, whereas verapamil '100 μM) increased VP-16 accumulation 2.05-fold When CCRF-CEM cells are preloaded with [ 3 H] VP-16 for 30 mm and then, without washing, treated with ardeemin derivatives for 30 min, the intracellular accumulation of VP-16 increased 3.9-fold by 30 μM of 5-N-Ac-ardeemin, 3.1-fold by 20 μM of ardeemin, and 4.2-fold by 100 uM of verapamil . IV. Drug Combinations and the Reversal of MDR For CCRF-CEM cells, vinblastine (VBL) and 5-N-acetyl- ardeemin (5NAc-Adm showed moderate synergism with regular tumor cells with maximal synergy. (Combination index Cl <1, =1, and >1 indicates synergism, additive effect, and antagonism, respectively.) For CCRF-CEM/VBL 100 cells resistant to VBL (220-fold resistant) and to many other drugs compared with CCRF-CEM cells, VBL + 5NAc-Adm (at 1:2000 combination ratio) showed marked synergism with CI=0.04, which allowed a 41- fold dose reduction for VBL, and a 55-fold dose reduction for 5NAc-Adm to achieve 98.4% inhibition of cell growth. Combination ratios from 1:2000 to 1:10,000 all showed synergism. This is apparently the strongest synergism among ever 100 a ticancer drug combinations examined so far using the quantitative combination index method. VinbJdfccine very effectively kills wild type cancer cells (e.g. CCRF-CEM) with IC 50 of 0.0017 μM. In combination with 5NAc -ωr t also kills drug resistant MDR cells (CCR?-CEM/VBL__„! with extremely strong synergism, which by far exceeded (> 10-fold) activity against wild type parent tv.nor cells (CCRF-CEM) . Table 1. Cylutoxic Effrcls of S N Acetylar eemin Analogs and Verapamil in Wild Type and MDR cells Table 1A. * Collaterally sensitive Table 2. Two Drug Combination Study of Vmblastme and 5-N-Acetylardeemιn on CCRF-CEM Cell Line at 72-HR Exposure Time. Based on XTT Assay. Drug A: VINBLASTINE (uM) Drug B: 5-N-ACETYLARDEEHIN (uM) Drug Parameters Dm H r A .00168 2.53519 .99212 B 18.79205 .78648 .98793 Cl values for actual experimental points of mixture of A and B at a non-constant ratio Mutually Exlusive Case Dose A Dose B Cl values for actual experimental points of mixture of A and B at a non-constant ratio Mutually Non-exclusive Case For P388 leukemic cells, the IC^ for Adr was reduced from 0.228 μM to 0.084 μM (2.7-fold reduction) in the presence of 0.42 μM of 5N-Ac-Ardm (IC 50 :43.7 μM). (See Table 2 A.) For P388/Dx leukemic cells (9.4-fold resistance to Adr), the IC 50 for Adr was reduced from 2.14 μM to 0.42 μM (5.1-fold reduction) in the presence of 2.80 μM of 5N-Ac-Ardm (IC 50 : 65.9 μM). (See Table 2B.) Table 2A. Drug Combination of Adriamycin and 5-N-Acetyl-Ardccnιin against P388 Cell Growth" Drug Combination Index Value at Parameters ED50 ED75 ED90 ED95 1C 50 (μM) 111 Adriamycin 5-N-Ac-Ard. Combination 0.409 0.355 0.306 0.277 (ratio = 1 :5) a. Cells (sensitive to adriamycin) were obtained from ATCC; 96 well microplate, 15,000 cell/well, N =2. Platting cells on day 1 , add drugs on day 2 and XTT assay on day 5. Table 2B. Drug Combination of Adriamycin and 5-N-Acetyl-Ardeemin against P388/DX Cell Growth" Drug Combination Index Value at Parameters ED50 ED75 ED90 ED95 ICso (μM) 111 Adriamycin 5-N-Ac-Ard. Combination 0.226 0.166 0.122 0.0994 (Ratio = 1:5) ±0.068 ±0.056 ±0.046 ±0.040 a. Cells resistant to adriamycin were obtained from Gleney; 96 well micropiate, 25,000 cell/well, N =2. Platting cells on day 1, add drugs on day 2 and XTT assay on day 5. Table 3. Two Drug Combination Study of Vi blastine and -N-Acetylardeemin on Vi blast1 ne-res l stant CC F- CEM Cell Line at 72-HR Exposure Time. Based on XTT Assay. Drug Parameters 0 m m .37101 2.39234 .99677 19.36733 1 .23325 .99592 Cl values for actual experimental points of mixture of A and B at a non-constant ratio Mutually Exclusive Case Cl values for actual experimental points of mixture of A and B at a non-constant ratio Mutually Non-exclusive Case Dose reduction index values for actual experimental points of mixture of A and B at a non-constant ratio Table 4. Two Drug Combination Study of Vmblastme and 5-N-Acetylardeemιn on Vinblastine-resistant CCRF- CEM Cell Line at 72-HR Exposure Time. Based on XTT Assay, (large-scale study) Drug A: VINBLASTINE CuM) Drug B: 5-N-ACETYLARDEEMIN C/-M) Drug Parameters ED50 ED75 ED90 ED95 Dπ jϊX) m r A .39341 1.73041 .98506 B 29.78891 1.10066 .98101 Cl values for actual experimental points of mixture of A and β at a non-constant ratio Mutually Exclusive Case Dose A Dose B .05 10 .025 10 .0' 10 .005 10 .0025 10 .001 10 Cl values for actual experimental points of mixture of A and B at a non-constant ratio Mutually Non¬ exclusive Case Dose A Dose B .05 .025 .01 .005 .0025 .001 Table 4A 1 3 Milo BDF mice werπ inoculπted wilh P388/0 10° cells/mouse i p at day 0 and treated by adriamycin 5 N acetyl ardeemin end verapamil starting day 1 QDX4 QWX2 TI ere were five mi c r ufy Jose ind te mice in control Adr adriamycin 5NAcArd 5 N nr etyl ordπemin VPML vorapamil AWC average weight change Survival time were recorded b ised on the t me of death with the following decimal valuoε 8AM 10 0) 1 PM (0 25} 5PM (0 51 % ILS % Increase in lifespan Verapamil 70mg/kg/day was for initial three doses and 35mg kg/day for the laεt five doβes Two mice died of toxicity of drugs on day 12 5 and 1 5 respectively Two mice died of toxicity of drugs on day 13 25 Three mice died of toxicity of drugs on day 4 5 1 4 5 and 1 5 5 respectively TABLE 4B COMBINATION THERAPY OF ADRIAMYCIN & 5-N-ACETY -ARDEEMIN OR VERAPAMIL IN B 6 D 2 F, MICE BEARING P388/DX TUMOR' ae mce were nocuae , ce smouse, p a ay , an reae y a amycn, - -ace -ar eemn an verapam startng ay 1, QDfl QWX2 There were five mice at every dose and ten mice in the roπtml Adr , adπamycin 5NAcArd , 5 N icet l ardeemin VPML vernpimil AWC avenge weigh! change Survival times were recorded bised on the time of death with the following decimal values 8AM (00), 1PM (025), 5PM (05) % ILS % increase in lifespan Verapamil 70mg/Kg/dιy was for initial three doses and 35mg/ g/day for the last five doses Two mice died of toxicity of drugs on day 14 One mouse died of toxicity of drugs on day 4 TABLE 4C COMBINATION THERAPY OF ADRIAMYCIN, VINBLASTINE AND DES-ME-N-ACETYL- ARDEEMTN IN B 6 D 2 F, MICE BEARING P388/0 TUMOR * a Male BDF mice were inoculated with P388/0, 10 cell/mouse, i p on day 0, and started treatment on day 1 , i p. , Q5Dx5, besides mice with dose VBL 3 0 mg/kg and VBL 3 Omg/kg + DMNAA 50mg g, only one injection i p , on day 1. There were five mice at every dose and ten in the control b Adr adriamycin, VB1 , vinbhslinc, DMNAA, 8 Des Me 5-N-acetyl-ardeemιn c AWC weight change d Surviv s were recorded Iπsed on the lime of death with the following decimal values 9 00 am (0 0), 1 00 pm (0 25), 5 00 pm (0 5) e MST mean survival time f % increase in lifespnn g One mouse died of loxicity of drug on day 9, and was excluded from calculation h Two mice died of loxicity of drug on day 5 and 6, and were excluded from calculation i One mouse died of toxicity of drugs on day 4, and was excluded from calculation j Three mice died of toxicity of drugs on day 4, 5 and 5 respectively, and were excluded from calculation N-Acetylardeemm is non-toxic to HCT116 cells at concentrations up to 2.2 μM At higher concentrations the material has diminished solubility N-Ac-adm at 2.2 μM was co-incubated with paclitaxel for 72 hr with HCT116 cells or the multidrug resistant (MDR) cell line HCT116 (VM) 46. The results are summarized m the table below. All drug exposures were for 72 hr and cytotoxicity was measured by XTT tetrazolium dye assay. Table 5. In Vitro Cytotoxicity Results for N- Acetylardeemm IC50 (nM HCT116 HCT116(V M) 46 P 'S ratio paclitaxel 2.0xl0 3 258 132 paclitaxel+N-Ac-adm 1.6xl0 3 14 9 These results suggest that a non-toxic concentration of 2.2 μM N-Ac-adm is able to substantially reverse paclitaxel resistance mediated by the P-glycoprotein efflux pump. This would be consistent with results seen with adriamycin in animals assuming resistance ir them was due to P-glycoprotein The degree of paclitaxel resistance ooserved m the presence of N-Ac-adm is comparable to the resistance observed with paclitaxel and 15 μM verapamil or 0.03% cremophor EL m HCT116(VM)46 cells (R/S ratio = 4) . Table 6. Inhibition of Cell Growth by Ardeemin Derivatives Human Acute Lymphoplastic T Cells Compounds CCRF-CEM CCRF-CEM/VBL (IC 50 in μM) Diketopiperazme 14(B) 147.9 147.2 N-Aceyl-Diketopiperazme 14(E) 225.1 540.9 5 -N-Acetylardeemin 17.18 6.99 Imde-Acetate 14(A) 48.11 39 gg Imide-BOC 14(C) 88.73 65.37 I ide-Diacetate 14(D) 62.53 37.14 Cells were preloaded with ['HlVinblastine for 1 5 mm washed 2 times (or without wash) with 100 ml cold medium to remove extracellular [ 3 HJVιnblastιne followed by 30 mm incubation at 37°C, with or without a reverse prenyl compound or an MDR reversing agent Cells were ther separated from radioactive medium by microfuge oil layer method Extracellular space counts carried down by cells ( 3 H Iπulin space) were subtracted from the total radioactive counts • -d σ. Discussion In principle, compounds 1, 2, and 3 could be obtained from the hypothetical tricyclic ammo acid 4 which is formally derived from tryptophan precursor 5 by alkylative cyclization (Figure 1; protection states of 4 and 5 are unspecified) . No method for achieving a transformation of the type 5 to 4 was known in the tryptophan series prior to the present invention The introduction of a 1, 1-dιmethallyl moiety at the gem- dimethyl carbon is unexpected in the art to afford a practical yield via direct alkylative cyclization (path a) In tne corresponding tryptamine series where the issue of stereochemical information transfer does not exist, two methods for the direct introduction of a 1,1- diethylpropynyl group have been reported to give a modest yield (Hmo, T., Hasum , K. ; Yamaguchi, H , Taniguchi, M. ; Nakagawa, M , Chem. Pharm. Bull. , 1985, 3_3, 5202; Nakagawa, M , Ma, J. ; Hmo, T , Heterocycles, 1990, 30 , 451) Direct alkylative cyclization of tryptamine derivatives with prenyl halides occurs exclusively at the primary carbon to give the undesired 3 , 3-dimethylallyl regioisomer (Bocchi, V , Casnati, G , Marchelli, R., Tetrahedron, 1978, 3_4, 929) The present inventors expecteα part D to be more useful wherein a heteroatom- mediate cxidative cyclization of 5 leaαs to 6 Numerous examples of protonic or oxidative cycl zations of the type 5 to 6 are known m both the tryptamine and tryptophan series However, these methods aid not provide efficient stereocontrol during cyclization (5 to 6) nor for subsequent activation in the substitution by the reverse-prenyl nucleophile (6 to 4) iHino, T , Nakagawa, M , in The Alkaloids , Brossi, A , eα , Academic Press, Ine , New York, 1988, 34, 1, Br nc o, M , Crich, D., J Org Chem , 1994, 59., 4239) Following suitable activation, a resultant cationoid species would serve to alkylate a reverse-prenyl nucleophile This strategy relies on an expected strong preference for « r - s - mteilocked 5,5-rιng system to enforce cis stereochem ¬ istry in both the oxidative cyclization and alkylation steps. Furthermore, this approach requires that ef- ficient transmission of stereαcnemical information from the tryptophan stereogenic center to the emerging junction n the heteroatom-mediated cyclization. The present invention implements these concepts in the total syntheses of 1, 2, and 3. The starting material used in the present method of preparing 1 was bis (Boc) tryptophan methyl ester 7 (Figure 4, prepared n two steps from L-tryptopnan : Franzen, H Grehn, .; Ragnarsson, U., J. Chem Soc , Chem Corπmun.. 1984, 1699 However, as used herein, 7 was preferably prepared from -tryptophan methyl ester by treatment with BOC 2 0 (3 equiv) , NaOH (5 equiv) , and NBu,HS0 4 (10 mol%) m CH 2 C1 2 (91% yield) . This compound reacted with N- phenylselenophthalimide (Nicolaou, K.C , Clare on, D.A.; Barnette, W.E.; Seitz, S.P. J Am Chem Soc . , 1979, 1Q1 , 3704) and catalytic p-toluenesulfonic acid to give a 78% yield of 3 -selenylated pyrroloindole 8 as an inseparable 9:1 mixture of diastereomers, following tne equilibration of an initial 1:1 mixture. Treatment of 8 with methyl triflate ana prenyl tributylstannane m the presence of 2 , 6-dι-ter -butylpyridine (Naruta, Y , ishigaichi, Y. ; Maruya a, K., Chem Lett. 1986, 1857) gave a 60% yield of 9, bearing the reverse prenyl group at the desired position as an unchanged 9:1 diastereomeπc mixture. unexpectedly, no products due to simple proton loss in the presumed benzylic cation intermediate were observed. (Witnout intending to be bounc to any mechanism, applicants suggest that this stability arises fro-n the reluctance of the ring system to approach planarity, wnerem the bulky Boc groups would be forced into close proximity l After saponificat on of 9 to acid 10, cnromatographic separation of the diastereomers was possible. In addition, the Boc groups could be simultaneously removed to give aminal 11, which was again isolated as a single diastereomer . Regarding the total synthesis of 1, BOP chloride-mediated coupling of 10 and the hindered amine 11 proceeded in 78% yield to give peptide 12. (Attempted couplings with other reagents were uniformly unsuccessful. For an additional example of a BOP chloride-mediated coupling of a hindered secondary amine where other reagents failed, see: Danishefsky, S.J.; Harrison, P.J.; Webb, R.R., ll ; O'Neil, B.T. , J. Am. Chem. Soc . , 1985, 107, 1421.) Removal of the remaining Boc groups with lodotnmethylsilane was accompanied by spontaneous cyclization to furnish directly, amauromme (1) m five linear steps from bis (Boc) -tryptophan methyl ester and an overall yield of 16%. The amauromine so produced was identical in all respects with an authentic sample of the natural material. Coupling of 10 with D-alanine methyl ester (Figure 5) , using standard agents afforded, m addition to the expected 13 , considerable amounts of a minor product presumably arising through epimerization of the " a- tryptophan" stereogenic center. Other attempted activating agents include DCC/DMAP, DCC/HOBT, isooutyl chlorofor ate, and BOP chloride. However, in situ generation of the acyl fluoride of 10 followed by its condensation with D-alanme methyl ester resulted in clean conversion (71%) to peptide 13. (Carpmo, .A. ; Mansour, E.-S.M.E.,- Sadat-Aalaee, D., J. Org. Chem. , 1991, 5_6, 2611) The diketopiperaz e 14 was obtained in 76% yield upon deprotection of 13 and ammonia-DMAP- duced cyclization. An intramolecular variant of the aza-Wittig reaction .Takeuch , H. ; Hagiwara, S.; Eguchi, S., Tetrahedron. 1989, 4_5, 6375) was used for efficient fusion of the (3H ) -quιnazolm-4 one sectoi Following acylation of 14 with o-azidobenzoyl chloride, the resultant 15 reacted with tributylphosph e in benzene to afford ardeemin ( 2 ) m 56% yield from 14. Finally, acylation of 2 provided 5-N-acetylardeemιn (3) in 11% overall yield for the total synthesis. The 5-N-acetylardeemin so provided was identical in all respects with an authentic sample of the natural material. The core structure of the three reverse-prenylated hexahydropyrrolomdole alkaloids was assembled rapidly and steroselectlvely (through hermodvna ic control) from a suitably presented tryptopnan in two steps. The value of tms approach was demonstrated by concise and efficient syntheses of 1, 2, and 3. Gypset The present invention also provides new analogues of gypsetm, as well as new compositions, methods of preparation of gypsetin and methods of pharmaceutical administration to inhibit the growth of MDR cells. However, the known use of gypsetm is to control cholesterol ^eveIs m vivo The gypsetm analogues provided herein are useful for treating subjects w th elevated cholesterol levels The regulation of cholesterol metabolism m humans is a ma;or focus of drug development Correlation between excess cholesterol and susceptibility to coronary heart α sease is row generally accepteα (Brown, M.S , Goldstein, J L. , Angew Chem , Int Ed Engl . , 1986, 25 , 583 j Interference either with the dietary absorption of cholesterol-containing foodstuffs or with the de novo b osy tnesis of cholesterol has been used to lower plasma cnclesterol content. Early strategies for containing hypercholesterole ia utilized the bile acid sequestrant cnolestyramme resin. (Lipid Research Clinics Program, J Am ed. Assoc. , 1984, 251, 351) However, the difficulties associated with this form of medication prompted a search for other approaches . A milestone in the contemporary management of cholesterol levels arose from the discovery of lovastatm, a powerful inhibitor of HiMG-CoA reductase. (Grundy, S.M., Cholesterol and Atherosclerois , Diagnosis and Treatment; Tower Medical : New York, 1990; p 4; Grundy, S. M. , New Enql . J. Med. r 1988, 319 , 24) This enzyme mediates the rate-limiting enzymatic step cholesterol biosynthesis. Agents based on the concept of HMG-CoA inhibition have proven to be effective n lowering both LDL and total cholesterol levels primary hypercholestemic patients. Inhibitors of squalene synthase such as the zaragozic acids have also been been identified as possible therapeutic agents but have not yet found clinical application. (Abe, I . ; Tomesch, J.C. , Wattanasin, S. ; Prestwich, G.D., Na . Prod. Rep. , 1994, il, 279.) Progression from abnormally high cholesterol levels to myocardial infarction presumably begins with the accumulation of intracellular estenfied cholesterol m macrophages . This is followed by subsequent foam cell formation and, ultimately, by the appearance of atherosclerotic plaques m arteries. (Sliskovic, D.R. ; Whige, A.D., Trends Pharamacol . Sci . , 1991, Y2_, 194.) The enzyme acyl CoA:cholesterol acyltransferase (ACAT) has been identified as the rate-limiting enzyme the absorption of cholesterol. Thus, the inhibition of ACAT nas received much attention due to its potential m moderating the effect of elevated cholesterol levels. -Sliskovic, D.R , White, A.D., Trends Pharmacol. Sci., 1991, 12, 194; Kumura, T. , Takase, Y.; Hayashi, K. ; Tanaka, H.; Ohtsuka, I.; Takao, Ξ., Kogushi, . ,- Yamada, T. ; Fujimori, T.; Saitou, I. , Akasaka, K., j. Med . r h p m 1993, 3_6, 1630.) Gypsetin (21) , recently isolated from Nanmzzia qγ p; a var. mcurvata IF0 9228, was found to be a competitive inhibitor of ACAT with respect to oleoyl-CoA with a K value of 5.5 μM. Inhibition of cholesterol ester formation in cultured macrophages with an IC 50 of 0.65 μM was observed. (Shinohara, C; Hasumi , K. ; Take , Y ■ Endo, A., J. Antibiot. , 1994, 4_7, 163; Nuber, B. ■ Hansske, F. ,- Shinohara, C. ; Miura, S . ; Hasumi, K.; Endo, A. , J. Antibiot., 1994, 47 . , 168.) An important structural aspect of gypsetin is the diketopiperazme moiety which is formally composed of two hypothetical amino acids 22 and 23, differing only in the relationship of the cis-fused [2, 3 -b] hexahydropyrrolo¬ dole chirality at C 3a and C βa to the S-configured amino acid center (C,) (Figure 7) . For the sake of convenience, 22 s referred to as the "pre-anti" system and 23 as the "pre-syn" moiety, anticipating the backbone relationship of the full heptacyclic ensemble of gypsetin itself. Constructs 22 and 23 share an obvious "L-tryptophan connection" provided that methodology could be developed for tne introduction of a 1 , 1 -dimethlyallyl (reverse prenyl) function at C : . In addition, cyclization of N b of the ammo acid side chain to C ^ of the mdole and hydroxylation at C 3 of the mdole through the agency of formal "OH would be necessary. Provided nere above, m connection with the synthesis of N-acetylardeemm, is a method foi the introduction of sucn a reverse prenyl group into tne C, a of a precuiit [2 , 3 -bl hexahydropyrrolomdole moiety. 'Marsden, 3.P. ; Depew, K.M , Danishefsky S.J., J Am Chem. Soc. , 1994, U , 11143 ' This transformation was accomplisned via a C. ^ ohenylseieno precursor. The present invention provides a method of introducing the reverse prenyl groups at C a and C 1]a and the hydroxyl functions at C s and C 15a of a gypsetin (21) , thus enabling a concise total synthesis of gypsetin and analogues thereof. The present invention provides a simple method to introduce the "reverse prenyl" function at C 2 of the indole in the presence of a suitably protected amino acid side cham. The oxidative conversion of 2,3-disub- stituted mdoles to chloromdolenines and the use of such chloromdolen es for functionalization of the carbon benzylic to C 2 was known. (Godtfredsen, W.O. ; Vanσedal S. , Acta Chem. Scand. , 1956, 1_0, 1414; Buchi, G. ,- Manning, R.E., J. Am. Chem. Soc . , 1966, 8J3, 2532 ; Owellen, R.J., J. Org. Chem. , 1974, 3_9, 69; Kutney, J.P.; Beck, J.; Byls a, F.; Cook, J.; Cretney, W.J.; Fuji, K.; Imhof, R.; Treasurywala, A.M., Helv. Chim. Acta. 1975, 58, 1690; Kuehne, M.E.; Hafter, R. , J. Org. Chem.. 1978, 43 , 3702 and references therein) A key issue was whether an intermediate such as 24 would have transient viability even if C 2 were unsubstituted. (For the only previously disclosed example of a carbon-based nucleophilic addition to a C 2 -unsubstιtuted chloroindolenme, see: Parsons, R.L. ; Berk, J.D.; Kuehne, M.E., J. Org. Chem. , 1993, 58, 7432., The mechanism for the conversion 24 to 25 could involve a two-step sequence (i.e. , addition to the imme and loss of HCI) . Compound 24 suffers nucleophilic attack at C ; leading to 25 and thereafter tautomerizes to 26 (Figure 8) . Application of this protocol allows for a rapid preparation of 2 , 3 -disubstituted indoles. The synthesis of gypsetin began with N-phthaloyl- tryptcpnan methyl ester (27; prepared from L-tryptophan metnyl ester by modification of a known method: Bodansky, M. ; Bodansky, A., The Practice of Peptide Synthesis ; Sprmger-Verlag: Berlin, 1984, p 10; Figure 9) , which was converted 95% yield to 28, following the a p proach described above, with prenyl-9-BBN as the nucleophile. (Kramer, G.W. ; Brown, H.C. , J. Qrαannmor Chem. , 1977, 132 , 9. The reaction of prenyl-9-BBN on the chloromdolenine (24) does not require the use of a catalyst; with other nucleophiles , catalysis is needed.) Hydraz olysis led to the C 2 -reverse prenylated tryptophan derivative 29. In addition, oxidative cyclization of a pre-constructed diketopiperazine (32) , stereochemically uncommitted with respect to the syn-anti issue, would be advantageous m the absence of diastereofacial control m the conversion of a system such as 30 to 22 or 23. Therefore, compound 29 was converted to 31 by first protecting the amine function with a BOC group and saponifying with LiOH/THF/MeOH/H 2 0. Coupling of 29 and 31 led, as shown, to diketopiperazine 32. A one-step conversion of diketopiperazine 32 to gypsetin (21) was attempted. A stereochemically random oxidative cyclization process would benefit from the concept that the hypothetical ratio of gypsetin to "syn"-"syn" product 33 and "anti" - "anti" product 34 would be 2:1:1. Many oxidants have been surveyed, but only one has proven to oe successful. Thus, reaction of 32 with 4 equiv of dimethyldioxirane afforded a 40% isolated yield of fully synthetic gypsetin (21) along with double syn product 33 (ca. 18%) and double anti product 34 ;ca. 20%) (Figure 10) . (For the reaction of Na-acylated indoles with dimethyldioxirane, see Zhang, X., and Fcote, C.S. , J. A . Chem. Soc. , 1993, 115, 8867; Adam, W., Ahreweiler, M. , Peters, K. , and Schmiedeskamp, B., J . Qrσ. Chem. , 1994, 59, 2733.) The spectral properties (-H NMR, 13 C NMR, MS, and IR) of synthetic gypsetin (21) were consistent with those of natural material. In addition, the chromatograpnic properties were identical, and the neltmg point was in accord with that reported for naturally derived material. The optical rotation of synthetic gypsetin was [ ] 24 D = -113.4° (c 0.20, CHC1 ) which was m good agreement with that of natural gypsetin, [a] 2 D = -116.9° (c 0.14, CHC1 3 ) . Accordingly, the total synthesis of gypsetm has been achieved. This synthesis can be conducted in as few as four steps from N-phthaloyltryptophan methyl ester (27) and is concise given the apparent complexity. (Diketo- piperazme 32 can be prepared directly, albeit in 35% yield, by heating tryptophan methyl ester (29) at 140°C for 3 h, thereby saving four steps the synthetic sequence described above.) Thus, chemistry developed here also serves to enhance methods for the synthesis of other complex mdoles. (There are relatively few direct methods for the preparation of 2, 3-disubstituted mdoles. For some methods, see Saulnier, M.G.; Gribble, G.W. , J. Org. Chem. , 1982, 4J7, 2810; Fukuyama, T.F.; Chen, X. ; Peng, G., J. Am. Chem. Soc, 1994, 116, 3127.) Table 7. Cytotoxicity of Gypsetin Isomers and 5-N- Acetylarαeem m Hamster Lung Cells Sensitive and Resistant to Actmomycm D Compound IC^ 0 for inhibiting cell growth (μM) DC-3F D C - 3F/SDII Gypsetin 3 78 2.25 Gypsetin, cis/cis 36 5 15.6 Gypsetin, trans/trans 13.8 11.3 N-Acetylardeemm 3.74 1.07 5 06 1.59 Adriamycin 0.03 0.38 00 a Male BDF m ce were nocu ate w t p388 0, 10E6 ce s mouse, P at Day 0, treated by adriamycin and 5 N acetylardeemin, starting Day 1 through Day 4, I daily b Drug A= adriamycin, Drug B= 5 N-acetylardeemin c MST- mean suivival time d %ILS- percent increase in Lifespan e Survival times were recoided based on the time of death with the following decimal values 8AM (0 0) , 1PM (0 25) , 5PM (0 5) §§ treate y adriamycin and 5-N-acetylardeemin, starting Day 1 through Day 4, I.P. daily. b. Drug A= adriamycin; Drug B= 5-N-acetylardeemin. c. MST= mean survival time. d. %ILS= percent increase in lifespan. e. Survival times were recorded based on the time of death with the following decimal values: 8AM (0.0), 1PM (0.25), 5PM (0.5) .

Claims: What is claimed is 1. A compound having the structure. wherein P , ?„ and R, are independently hydrogen, OH, NH,, SH, nalogen, C^ C linear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, halophenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxybenzyl; wherein R 0 and R 2 are independently hydrogen, OH, C λ - C 9 linear or branched cham alkyl, -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 0H, -CR 3 R 3 -CH(0H)R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydrogen, halogen, Ci-C,, linear or branched chain alkyl, phenyl, alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl or benzyl; wherein R s is nyαrogen, I -C 3 lmear or brancned chain alkyl, phenyl, aκylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, dolylmethyl, alkylmercapto, or arylmercapto; and wherem R 8 is hydrogen, C,-C, lmear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxy¬ benzoyl, benzyl or C -C 9 linear or branched chain alkyl; with the proviso that (a) when R 2 s -CR ^ R j - CH(0)CH 2 , -CR 3 R 3 -CH 2 CH,, -CRjR,-CH 2 CH 2 0H, -CR 3 R 3 -CH(OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then R 0 is hydrogen, (b) when R 0 is -CR R 3 -CH(0)CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R,-CH 2 CH 2 OH, -CR 1 R,-CH(OH) R 4 or -CR R 3 -CH=CHR 4 , then R 2 is OH; and (c) wnen d) R 0 or R 2 is -CR 3 R 3 -CH=CHR,, (n) R 3 and R 5 are CH 3 and ( m ) R s is hydrogen , then R, , R 6 an d R are not al l hydrogen . The compound of claim 1 having the structure : 5 The compound of claim 2 where R 0 is hydrogen 4. The compound of claim 1, wherem R 0 , R lf R 3 , R^, R 6 and R 7 hydrogen; wherein R 2 is -CR 3 R 3 -CH=CHR 4 ; wherein R. is CH 3 ; and where R e is -(C=0)CH 3 . 5. A composition comprising an amount of the compound of claim 1 effective to inhibit the growth of multidrug resistant cells and a pharmaceutically acceptable carrier. 6 The composition of claim 5, furtner compris ng a cytotoxic agent . " " The composition of claim 6, wnerem the cytotoxic agent is an anticancer agent. The composition of claim 7, wherein the anticancer agent is adriamycin. Tne composition of claim 7, wherein the anticancer agent is vmblastme. .0 The composition of claim 7, wherem the anticancer agent is paclitaxel 11 The composition of claim 7, wherem R, is -CR 3 R 3 -CH=CHR, ; where R l R * and R 7 are hydrogen; wherem R, and R ς are CH, and wherem R R is - (C=0) CH,. 12. The composition of claim 5, where the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 13 The composition of claim 5, wnerem the effective amount is between about 0.1 mg/kg to about 10 mg/kg of body weight. 14. A compound having the structure wherein R j is hydrogen, OH, NH,, SH, halogen, C, -C 9 linear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkyl¬ phenyl, dialkylphenyl, alkoxyphenyl, hydroxypnenyl or oenzyl , wherein R α and R r are independently nydrogen, OH, Cj-C, linear or brancned chain al yl, -CR,R -CH(0; CH, , -CR 3 R 3 -CH 2 CH, , CR 3 F,-CH 2 CH_0H , -CR 3 R,-CH(OH) R, or -CR,R 3 -CH=CHR„ , wherem R, s hydrogen, - CR,R, - CH ( O ) CH, , - CR 3 R, - CK.CH 3 , -CR 3 R 3 -CH,CH,OH, -CR.R,-CH(OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydroσen halogen, C^ C linear or branched chain alkvl phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherein R 7 is hydrogen, halogen, C,-C 9 line-r or branched chain alkyl, alkylmercapto, alkylamino dialkylamino, alkoxy, phenyl, alkylphenyl, dialky l ¬ phenyl, alkoxyphenyl, hydroxyphenyl or benzyl ; wherein R e is C^C, linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl or C^C, linear or branched chain alkyl; and wherein R 9 is hydrogen or OH ; with the proviso that (a) when R 0 is -CR 3 R,-CH (O) CH,, -CR 3 R 3 -CH 2 CH 3/ -CR 3 R 3 -CH,CH,OH, -CR 3 R,-CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 , then (i) R 5 is H, (ii) R s is -CR 3 R 3 - CH(0)CH 2 , -CR 3 R 3 -CH,CH 3 , -CR 3 R 3 -CH : CK,0H, -CR,R 3 -CH (OH) R, or -CR 3 R 3 -CH=CHR and (iii) R, is OH; and (b) when R s is -CR 3 R 3 -CH(0)CH 2 , -CR 3 R 3 -CH,CH 3 , -CR,R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH(OH)R 4 or -CR 3 R 3 -CH=CHR 4 , then (i) R 0 is hydrogen, (ii) R 6 is -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH 2 CH,, -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH(OH) R 4 or -CR 3 R 3 -CH=CHR 4 and (iii) R 9 is OH; and (c) both R. and R 7 are not hydrogen. 15. A composition comprising an amount of the compound of claim 14 effective to inhibit the growth of multidrug resistant cells and a pharmaceutically acceptable carrier. 16. The composition of claim 15, further comprising an amount of a cytotoxic agent. 17. The composition of claim 16, wherem the cytotoxic agent is an anticancer agent . 18. The composition of claim 17, where the anticancer agent is adriamycin. 19 The composition of claim 17, wherein the anticance r agent is vinblastine. 20. The composition of claim 17, wherein the anticancer agent is paclitaxel. 21. The composition of claim 16, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 22. The composition of claim 16, where the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight. 23. The comDound of claim 14 havmα tne structure OK 24. A comoounα hav σ the structure: wherein R : is hydrogen, OH, NH,, SH, halogen, c -c linear or branched chain alkyl, alkylmercapto alkylamino, diaikylammo, alkoxy, p enyl alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxy ¬ phenyl, benzyl, or hydroxybenzyl; wherein R c and R 2 are independently hydrogen, OH, -c, linear or branched chain alkyl, -CR 3 R 3 -CH (0) CH,, -CR 3 R 3 -CH CH -CR 3 R 3 -CH,CH,OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR ; wherein R, and R 4 are independently hydrogen, halogen, -C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherein R 5 is hydrogen, -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialk- oxybenzyl, indolylmethyl, alkylmercapto, or aryl¬ mercapto; and wherein R' and R" are independently hydrogen, C l -C 9 linear or branched chain alkyl, C : -C 9 linear or branched chain acyl, benzoyl, alkylbenz¬ oyl, dialkylbenzoyl, alkoxybenzoyl, or benzyl; with the proviso that (a) when R, is -CR 3 R 3 -CH(O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH,OH, -CR,R 3 -CH (OH) R 4 or -CRR 3 -CH=CHR 4 , then R 0 is hydrogen; and (b) when R 0 is -CR,R 3 -CH(0)CH,, -CR 3 R 3 -CH,CH 3 , -CR 3 R 3 -CH,CH,OH, -CR 3 R 3 -CH(OH)R 4 or -CR 3 R 3 -CH=CKR, , then R, is OH. The comDOund of structure : O 26. A composition comprising an amount of tne compound of claim 24 effective to inhibit the growtn of multidrug resistant cells and a pharmaceuticallv acceptable carrier. 27. A composition of claim 26, further compr smci an amount of a cytotoxic agent. 28. The composition of claim 27, wherem the cytotoxic agent is an anticancer agent. 29. The composition of claim 28, wherein the anticancer agent is adriamycin. 30. The composition of claim 28, wherem the anticancer agent is vmblastme. 31. The composition of claim 28, wherein the anticancer agent is paclitaxel. 32. The composition of claim 26, wherem the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 33 The composition of claim 26, where the effective amount of the compound is between about 0.1 πg/kα to about 10 mg/kg of body weign . 34. A method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of the compound of claim 24 effective to inhibit the growth of multidrug resistant cells comn ation with a pharmaceutically acceptable carrier. 35 . The method of claim 34 , further comprising admin¬ istering an amount of a cytotoxic agent . 36. The method of claim 35, wherein the cytotoxic aαe ι - is an anticancer agent. I -? . The method of claim 36, wherein the anticancer agent is adriamycin. 38. The method of claim 36, wherem the anticancer acyent is vmblastme. 39. The method of claim 36, wherem the anticancer agent is paclitaxel. 40. The method of claim 34, where R, is -CR 3 R 3 -c:-_=CHR • wherem R 0 , R ' and R ' are hydrogen; and wnerem R is CH 3 . 41. The method of claim 34, wherem tne compound has the structure : and wherem R 0 , R R 4 , R and P are hydrogen; wherein R 2 is -CR 3 R 3 -CH=CHR 4 , and wherein R 3 and R s are CH, . The method of claim 34, wherein tne effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 43. The method of claim 34, wnerem the effective amount of the compound is between accut 0 1 mg/kg to about 10 mg/kg of body weight. 44. A process for synthesizing an N-acyiardeemm having the structure: wherem R L s hydrogen, OH, NH,, SH, halogen, C^ , linear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, halo¬ phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, halophenyl, benzyl, or hydroxybenzyl; wherein R 3 and R 4 are independently hydrogen, halogen, C -C 9 lmear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wnerein R 5 is hydrogen, C,-C q linear or branched chain alky , pnenyl, alkylphenyl, dialkylpnenyl, al oxypnenyl, oenzyl, alkoxybenzyl, dialkoxyoenzyl, dolyimethyi, alkylmercapto, or arylmercapto; wnerein R s and R 7 are independently hydrogen, halogen, Cj . -C, lmear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxypnenyl or benzyl; and where R 9 is C,-C 9 lmear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; which comprises: ( a ) (i) reacting a compound having the structure- wherein X is Br, Cl, F, I, mesylate, triflate, tosylate, perchlorate, hydrogensulfate, carbonate, bicarbonate or tetrafluoroborate; and R is C x -C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy ¬ phenyl, benzyl or alkoxybenzyl, with an acyl halide having the structure R,(C=0) -Z, wherein Z is F, Cl, Br or I, or an acyl anhydride having the structure [R 0 (C=0) ] ,0, wherein R 0 is C^C, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, or 9-fluorenemethyl, to form a dicarbamate having the structure: ii) treating the dicamamate formed in step [ a ) (i) with a suitable phenylselenide reagent to form a mixture of phenylselenide dicarbamates having the structures: R ORπ °R- OR n OR, wherem R 2 is phenyl, A -C 9 alkylphenyl, dialkylphenyl or trialkylphenyl; and (iii) cross-coupling the mixture of phenyl¬ selenide dicarbamates formed in step (a) (ii) with (1) an organostannane having the structure R 3 R 3 C=CHCHR 4 ΞnR'R' 'R' ' ' wherein R 3 and R 4 are independently hydrogen, halogen, Cj_-C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; and wherem R' , R' ' and R' ' ' are independently a C.-C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, or (2) a Grignard reagent having the structure Z 0 MgR 3 R 3 C-CH=CKR, and an organometallic catalyst having the structure NiQ 2 (FR l V, 2 where Q and Z Q are independently F, Cl, Br or I and R 1V s lmear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, to form a mixture of cross-coupled dicarbamates respectively having the structure.- z R OR D OR (i) hydrolyzing the mixture of cross-coupled dicarbamates formed in step (a) (iii) to form a mixture of dicarbamate acids; (ii) purifying the mixture of dicarbamate acids formed in step (b) (i) ,- and (iii) isolating the dicarbamate acid having the structure: OR D OR, (c) coupling the dicarbamate acid with an amino acid ester having the structure: R<; H.N . O R, wherein R 9 is C L -C 9 lmear or branched chain alkyl , phenyl , alkylphenyl , dialkylphenyl , alkoxyphenyl, or benzyl; to form a peptide dicarbamate having the structure : (d) (i) deprotecting and lactamizing the peptide dicarbamate formed in step (c) to form a diketopiperazme having the structure: D_ (ii) acylating the diketopiperazme formed in step (d) (i) with a compound having the structure : wherein Y is Cl, Br, F or I, to form an N- benzoylated diketopiperaz e having the structure : (iii) cyclizing the compound formed in step 15 (d) (ii) to form an ardeemin having the structure : and (iv) acylating the ardeemin formed m step (d) (ui) with (A) an acyl halide having the structure R 8 (C=0) -Z' wherein (1) R s is hydrogen and Z' is OR where R is a C : -C, lmear or branch chain alkyl, phenyl, alkylphenyl, dialkyl¬ phenyl, alkoxyphenyl, hydroxyphenyl or benzyl; 35 or (2) wherein R, is C,-C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl, and Z' is Cl, Br, F, I, or OR where R is a linear or branch chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl or benzyl; or with (B) an acyl anhydride having the structure [R 8 (C=0)] 2 0, wherein R 8 is hydrogen, C^ C ? linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl or benzyl, to form an N-acylardeemin. 45. The process of claim 44, wherein R lr R 6 and R 7 are hydrogen. 46. The process of claim 44, wherein R 0 is t-Bu, R and R 5 are CH 3 , and X, Y and Z are Cl . 47. The process of claim 44, wherein R 8 is CH 3 . 48. The process of claim 44, wherein R 3 is CH 3 and R < is hydrogen. 49. The process of claim 44, wherein R 2 is phenyl. 50. The process of claim 44, wherein R' , R' ' and R' ' ' are n-Bu. 51. A method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of an ardeemin effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein the ardeemin has the structure: wherein R. , R 6 and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, C 1 -C 9 linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alk¬ oxy, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl, hydroxyphenyl, benzyl, or hydroxybenzyl,- wherein R 2 is hydrogen, linear or branched chain alkyl, -CR 3 R 3 -CH(O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH(OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R < are independently hydrogen, halogen, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl or benzyl; wherein R 5 is hydrogen, linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, alkoxybenzyl, dialkoxybenzyl, indolylmethyl, alkylmercapto, or arylmercapto; and wherein R β is hydrogen, C j -C, linear or branched chain acyl, benzoyl, alkyl¬ benzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl or C.- C 9 linear or branched chain alkyl . 52. The method of claim 51, further comprising admin¬ istering an amount of a cytotoxic agent. 53. The method of claim 52, wherein the cytotoxic agent is an anticancer agent. 54. The method of claim 53, wherem the anticancer agent is adriamycin. 55. The method of claim 53, wherein the anticancer agent is vinblastine. 56. The method of claim 53, wherein the anticancer agent is paclitaxel. 57. The method of claim 51, wherein the ardeemin has the structure : 58. The method of claim 57, wherein the ardeemin is N- acetylardeemin. 59. The method of claim 57, wherein R 2 is -CR 3 R 3 -CH=CHR 4 • where R l t R 3 , R 4 , R β and R 7 are hydrogen; wherein R s is CH 3 ; and wherein R 8 s H. 60. The method of claim 51, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 61. The method of claim 51, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight. A method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of a compound effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein the compound has the structure: wherein R x and R 7 are independently hydrogen, OH, NH 2 , SH, halogen, Cj-C, linear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl, hydroxyphenyl or benzyl, wherein R 0 and R 5 are independently hydrogen, OH, C^C, linear or branched chain alkyl, -CR 3 R 3 -CH (O) CH,, -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 6 is -CR 3 R 3 -CH (O) CH 2 , -CR 3 R 3 -CH 2 CH 3 , -CR 3 R 3 -CH 2 CH 2 OH, -CR 3 R 3 -CH (OH) R 4 or -CR-R 3 -CH=CHR < , wherein R 3 and R 4 are independently hydrogen, halogen, C^C, linear or branched chain alkyl, phen¬ yl, alkylphenyl, dialkylphenyl, alkoxyphenyl or ben¬ zyl; wherein R B is hydrogen, C--C, linear or branched chain acyl, benzoyl, alkylbenzoyl, dialkylbenzoyl, alkoxybenzoyl, benzyl or C λ -C 9 lmear or branched chain alkyl, and wherem R 9 is hydrogen or OH. The method of claim 62, further comprising admin¬ istering a cytotoxic agent 64. The method of claim 63, wherein the cytotoxic agent is an anticancer agent. 65. The method of claim 64, wherein the anticancer agent is adriamycin. 66. The method of claim 64, wherein the anticancer agent is vinblastine. 67. The method of claim 64, wherein the anticancer agent is paclitaxel. 68. The method of claim 62, wherein R,, R 7 and R 8 are hydrogen; and wherein R 3 is CH 3 . 69. The method of claim 68, wherein the compound has the structure : R OH 70. The method of claim 62, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 71. The method of claim 62, where the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight. 72 A method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of an amauromine effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier wherein the amauromine has the structure: R wherein R 0 and R 7 are independently hydrogen, OH, H 2 , SH, halogen, C 1 -C 9 linear or branched chain alkyl, alkylmercapto, alkylamino, diaikylammo, alkoxy, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, hydroxyphenyl, benzyl, or hydroxy¬ benzyl; wherein R : and R 2 are independently hydrogen, C x -C 9 linear or branched chain alkyl, -CR 3 R 3 -CH(O) CH 2 , -CR 3 R 3 -CH 2 CH 3 ' - CR 3 R 3 - CH 2 CH 2 OH , -CR 3 R 3 -CH(OH)R 4 or -CR 3 R 3 -CH=CHR 4 ; wherein R 3 and R 4 are independently hydrogen, halogen, Cl-C 9 linear or branched chain alkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxy¬ phenyl or benzyl; and wherein R 5 and R* are independ¬ ently hydrogen, C 3 -C 9 linear or branched chain alkyl, acyl, acylalkyl, phenyl, alkylphenyl, dialkylphenyl, alkoxyphenyl, benzyl, benzoyl, alkylbenzoyl or dialkylbenzoyl . 73. The method of claim 72, further comprising admin¬ istering a cytotoxic agent. 74. The method of claim 73, wherein the cytotoxic agent is an anticancer agent. 75. The method of claim 74, wherein the anticancer agent is adriamycin. 76. The method of claim 74, wherein the anticancer agent is vinblastine. 77. The method of claim 74, wherein the anticancer agent is paclitaxel. 78. The method of claim 72, wherein R c , R 5 , R e and R 7 are hydrogen. 79. The method of claim 72, wherein R 3 and R 2 are -CR 3 R 3 -CH=CHR,; wherein R 3 is CH 3 ; and wherein R 4 is hydrogen. 80. The method of claim 70, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight. 81. The method of claim 70, wherein the effective amount of the compound is between about 0.1 mg/kg to about 10 mg/kg of body weight.

Inventors: BORNMANN WILLIAM, CHOU TING-CHAO, DANISHEFSKY SAMUEL, DEPEW KRISTOPHER, MARSDEN STEPHEN P, SCHKERYANTZ JEFFREY, WOO JONATHAN C G, ZATORSKI ANDREJ, BORNMANN, WILLIAM, CHOU, TING-CHAO, DANISHEFSKY, SAMUEL, DEPEW, KRISTOPHER, MARSDEN, STEPHEN, P., SCHKERYANTZ, JEFFREY, WOO, JONATHAN, C., G., ZATORSKI, ANDREJ
Applicants: BORNMANN WILLIAM, CHOU TING CHAO, DANISHEFSKY SAMUEL, DEPEW KRISTOPHER, MARSDEN STEPHEN P, SCHKERYANTZ JEFFREY, SLOAN KETTERING INST CANCER, UNIV COLUMBIA, WOO JONATHAN C G, ZATORSKI ANDREJ, BORNMANN, WILLIAM, CHOU, TING-CHAO, COLUMBIA ENGINEERING ENTERPRISE, DANISHEFSKY, SAMUEL, DEPEW, KRISTOPHER, MARSDEN, STEPHEN, P., MEMORIAL-SLOAN KETTERING CANCER CENTER, SCHKERYANTZ, JEFFREY, WOO, JONATHAN, C., G., ZATORSKI, ANDREJ
Application year: 1996
Main classification: C07D487
IPC codes: A61K31, A61P35, C07D487