PHOSPHENE OXIDE-TERMINATED ALLENE-ENE-YNE DNA-CLEAVING, ANTITUMOR AND ANTIBIOTIC MOLECULES

Abstract: Phosphene oxide-terminated allene-ene-yne compounds are disclosed that possess DNA-cleaving, antimicrobial and tumor growth-inhibiting properties. Methods of making and using those compounds are also disclosed.

Description: PHOSPHENE OXIDE-TERMINATED ALIENE-ENE-YNE DNA-CLEAVTNG, ANTITUMOR AND ANTIBIOTIC MOLECULES Description Technical Field The present invention relates to novel DNA- cleaving, antibiotic and antitumor compounds, and particularly to molecules that contain a phosphene oxide-terminated allene-£i£ « -ene-yne functionality. Background Art Natural products have been capturing the interest and imagination of isolation, synthetic, and medicinal chemists for a very long time due to their fascinating structures and biological activities. Man- designed molecules ("designer molecules*-) with predefined chemical and biological properties could enrich and complement this arsenal of substances, and sharpen the capability of chemistry to deliver biologically and therapeutically useful compounds. Described herein are the design, synthesis, chemical and biological actions of novel designer molecules vith DNA cleaving and antitumor properties; for some recent examples of designed DNA-cleaving molecules, see: (a) Nicolaou et al., Am. Chem. Soc . 11£:7247 (1988); (b) Nicolaou et al., Anoev. Chem. Int. Ed- Enαl.. 2£:l272 (198 * 9); (c) Povsic et al., J. Am. Chem. Soc. 111:3059 (1989); (d) Hertzberg et al., ___ Am. t__em. Soc. l££:313 (1982); (e) Moser et al., Ssifinffife, 22.1:645 (1987); (f) Corey et al., J. Am. Chem. SPg., 111:8523 (1989); (g) Pyle et al., J. Am. chem. S?gι# 111:4520 (1989); (h) Sigman, J. Am. Chem. Soc. 111:4941 (1989); (i) Ohno at al., J. Am. Chem. Soc. 112:0000 (1990; (j) Danishefs y, J. Pro. Chem. soc. ≤l:2781 (1989). In addition, Nagata et al., Tetrahedron Lett.. .10:4995 (1989) reported synthesis of a molecule that contained an allene-ene-yne functionality that also contained a phosphene oxide group. That phosphene oxide was bonded to the allene group proximal to the double bond, as compared to the compounds described hereinafter in which the phosphene oxide group is bonded to a terminal position of the allene group, distal to the double bond. No biological studies were reported by Nagata et al. In addition to the man-made DNA cleaving compounds, naturally occurring ene-diyne compounds have also been reported and studied. Included among the naturally occurring enediynes are calicheamicin and esperimicin that have substantially identical aglycon portions but different sugar portions [(a) Lee et al., J. Am. Chem. Soc. 109:3464. 3466 (1987); (b) Nicolaou et al., J. Am. Chem. Soc . 110:7247 (1988); (c) Hawley et al., Proc Natl. Acad. Sci. USA. 6 1105 (1989); (d) Golik et al., J. Am. Chem. Soc. 109:3461. 3462 (1987) ] and neocarzinostation that also contains sugar- derivative side chains [(a) Edo et al., Tetrahedron Lett.. 26:331 (1984); (b) Chin et al., Biochemistry. 22:8106 (1988); <c) Lee et al., Biochemistry. 28:1019 (1989)]. Brief Summary of the Invention The present invention relates to phosphene oxido-ter inated allene-ene-yne compounds that have DNA- cleaving, antimicrobial and tumor growth-inhibiting activites. A compound of the invention is a diphenl- (1,-8-disubstituted-octa-2,3,5-trien-7-yne)phosphene oxide having a generalized structure as shown below wherein Ph is phenyl; R 1 and R 2 are hydrogen (H) or R 1 and R 2 together with the unsaturated carbon atoms bonded thereto (the depicted intervening vinylidene group) form a mono- or bicyclic aromatic ring; R 3 is hydroxyl or C,-C 6 acyloxy; and R 4 is hydroxymethyl, C 1 -C 6 acyl hydroxymethyl or phenyl. Where R 1 and R 2 together with their bonded unsaturated carbon atoms form a mono- or bicyclic aromatic ring, that ring is preferably a benzo or naphtho ring. It is also preferred that R 3 be hydroxyl and that R 4 be hydroxymethyl or phenyl. A pharmaceutical composition is also contemplated herein. Here, a before-described compound is dissolved or dispersed in a physiologically tolerable diluent in an amount effective for a desired effect such as DNA cleaving, as an antimicrobial or to inhibit tumor growth. A method of cleaving DNA, inhibiting tumor growth or killing microbes is also contemplated. Here, a composition as described above is contacted with the DNA to be cleaved, target tumor cells whose growth is to be inhibited or target microbial cells to be killed. That contact is maintained for a time period sufficient for the desired result to be obtained. A composition can be administered repeatedly. Brief Description of the Drawings In the drawings forming a portion of this disclosure, Figure 1 shows a reaction scheme (Scheme 1) that illustrates a mechanistic rationale for the preparation of a compound of this invention (III) and its reaction in DNA cleavage by paths a or b. In this scheme, R 1 and R 2 are generalized εubstituentε that are specifically disclosed herein as CH 2 R 3 and R 4 , respectively, X is phosphorous or sulfur and n is one for sulfur or two for phosphorous, and Ph is phenyl. Bracketed structures are proposed intermediates, and curved arrows show positions of bond rearrangement and attack by DNA. Figure 2 shows a reaction scheme (Scheme 2) that illustrates the cyclization reactions of a number of compounds of the invention. In this scheme, Ph is phenyl, R, and R 2 are CH 2 R 3 and R 4 as defined hereinafter, and Si t BuMe 2 is t-butyldimethylεilyl. Figure 3 shows a reaction scheme (Scheme 3) for the preparation of compounds of the invention via intermediate compounds. Parenthesized percentages are yields in each step shown. R groups are as shown, with Ph and Si t BuMe 2 being as defined before. Figure 4 in three panels (Fig. 4a, 4b and 4C) are photographs of ethidium bromide stained 1 percent agarose gels that illustrate cleavage of φX174 form I DNA by compounds of the invention after 48 hours at the temperatures shown. Lane 1 of each panel is the starting DNA. Lanes 2-5 of each panel contained Compounds lb, 2b, 3b and 4b, respectively, present at 1000 μM at a pH value of 8.5. The numerals I, II and III to the left of Fig. 4a show the migration positions of DNA forms I, II and III, respectively. Figure 5 is a photograph of crystal violet stained cell cultures of MIA PaCa-2 human pancreatic carcinoma cells that illustrate the inhibition of growth after four days of those cells by the shown concentrations of Compound 4b. Figure 6 shows results similar to those of Figure 5 using Compound lb. Figure 7 is a graph that shows the percentage of control cell staining of MIA PaCa-2 human pancreatic carcinoma cells after four days of growth in the presence of Compounds lb-4b. In this graph, data points are shown as follows: Compound lb = solid squares; Compound 2b = open circles; Compound 3b - closed circles; and Compound 4b = open squares. Detailed Description of the Invention I. Background Scheme 1 of Figure 1 depicts the mechanistic rationale for the formation and action of these new class of compounds. Thus, it was hypothesized that propargylic compounds of type I may be induced to rearrange to the conjugated allenic systems III under the influence of PhSCl or Ph 2 PCl via intermediates II. Structures III were then expected to undergo a Meyers cyclization reaction [(a) Meyers et al., J. Am. Chem. Soc.. 111:8057 (1989); (b) Meyers et al., J. A . Chem. Soc.. 111:9130 (1990); (c) Kappen et al., J. Am. Chem. So . 112:2797 (1990)] to form radicals IV (path a) or undergo nucleophilic attack originating from DNA to form species V (path b) as expected from recent results with propargylic and allenic εulfones. [Nicolaou et al., Angew Chem. Int. Ed. Enσl.. £8:1272 (1989)]. Either pathway should cause cleavage of DNA. Sulfur compounds of type III were found to be rather labile and not suitable for practical DNA, antibiotic or antitumor activity studies. The phosphorus series, however, proved to be easily prepared and handled, and exhibited the properties of DNA cleavage and antitumor activity in the temperature range of 37-47°C as discussed herein. II. The Compounds A compound of the invention is a diphenyl- (1,8-diεubεtituted-octa-2,3,5-trien-7-yne)phosphene oxide, or a 5(6)-position fused ring derivative thereof. A generalized structure for such a compound is illustrated in εtructural Formula I εhown below: wherein Ph is phenyl; R 1 and R 2 are hydrogen (H) or R and R 2 together with the unsaturated carbon atoms bonded thereto (intervening vinylidene group) form a mono- or bicyclic aromatic ring; R 3 is hydroxyl or C 1 -C 6 acyloxy; and R 4 is hydroxymethyl, C,-C 6 acyl hydroxymethyl or phenyl. It is seen that the allenic and acetylenic groups are in a cis relation to each other. Conversely, it can be said that the 5- and 6-position R 1 and R 2 groups are in a cis relation about the 5-double bond. In accordance with the above formula, the 5-position double bond can also be shared with an aromatic ring system that contains one or two fused rings. Those ring systems include substituted and unsubstituted benzene, naphthalene, pyridene, quinoline, isoquinoline, pyrazine, quinoxaline, benzofuran, furan, thiophene, oxazole, pyrimidene, benzothiophene, isobenzofuran, isobenzothiophene, N-C 1 -C 6 alkyl indole, N-C 1 -C 6 alkyl isoindole, N-C 1 -C 6 alkyl benzimidazole and benzoxazole. A "N-C 1 -C 6 alkyl" group in an above designation is a C 1 -C 6 alkyl group bonded to a secondary nitrogen atom in an appropriate aromatic ring. Exemplary C 1 -C 6 alkyl groups include methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, pentyl, hexyl, 2-methylhexyl, cyclopentyl and cyclohexyl. An above aromatic ring system can itself also be substituted at one or all of the available positions; i.e., at a position other than those shared with the 5(6)-double bond. Exemplary substituent groups include C 1 -C 6 alkyl, hydroxyl, C,-C 6 alkoxy, C 1 -C 6 acyloxy, nitro and halo other than iodo; i.e., fluoro, chloro or bromo. A before-mentioned C 1 -C 6 acyloxy group is a radical formed by esterification of a hydroxyl group of a before-discussed allene-ene-yne phosphene oxide derivative with a C 1 -C 6 carboxylic acid. Exemplary C 1 -C 6 acyloxy groups include formoxy, acetoxy, propionoxy, hexanoyloxy and cyclopentancarboxy. Of the above compound types, it iε preferred that R 1 and R 2 be hydrogen, or together with the 5-poεition double bond (the intervening vinylidene group) form a benzene or naphthalene ring. It is also preferred that R 3 be hydroxyl and that R 4 be hydroxymethyl or phenyl. Particularly preferred compounds include: a) 2-Diphenylphosphoroεo-nona-2,3,5-trien-7- yne-l,9-diol; i.e., a compound of Formula I in which R and R 2 are hydrogen, R 3 iε hydroxyl and R 4 is hydroxymethyl (Compound lb) ; b) 2-Diphenylphoεphoroεo-8-phenyl-octa- 2,3,5-trien-7-yn-l-ol; i.e., a compound of Formula I in which R 1 and R 2 are hydrogen, R 3 iε hydroxyl, and R iε phenyl (Compound 4b) ; c) 1-(3-Diphenylphoεphoroεo-3-hydroxy-prop- 1,2-dienyl)-2-(3-hydroxy-prop-l-ynyl)benzene; i.e., a compound of Formula I in which R 1 and R 2 together with the intervening double bond form a benzene ring, R is hydroxyl, and R 4 is hydroxymethyl (Compound 2b) ; and d) 2-(3-Diphenylphosphoroso-3-hydroxy-prop- 1,2-dienyl)-3-(3-hydroxy-prop-l-ynyl)naphthalene; i.e. , a compound of Formula I in which R 1 and R 2 together with the intervening double bond form a naphthalene ring, R 3 is hydroxyl, and R 4 is hydroxymethyl (Compound 3b). III. Compound Syntheses A compound of the invention can be readily prepared. A generalized synthetic scheme (Scheme 3) for the preparation of Compounds lb, 2b, 3b and 4b iε shown in Figure 3. It is noted that subscripted R groups are utilized in Scheme 3 rather than superscripted R groups to differentiate the R groups of the scheme from those εuperscripted R groups discussed before. The compounds illustrated are neverthelesε the same. Thus, an appropriate hydroxymethylvinyl iodide, e.g., l-iodo-3-hydroxy-prop-l-ene, 2-iodobenzyl alcohol or 3-iodo-2-naphthyl alcohol (Compounds 5-7), iε reacted with a slight excess of an appropriate acetylene derivative such as t-butyldimethylsilyl (TBS) propargyl alcohol or phenylacetylene in the presence of triphenylphospene, palladium" chloride, cuprous iodide and diethylamine to form a conjugated ene-yn-ol (Compoundε 8-11) . The alcohol portion of that molecule iε oxidized to the correεponding aldehyde aε with manganeεe dioxide. The aldehyde iε then reacted with TBS propargyl alcohol in the presence of a strong base such as butyl lithium to form an alcohol containing one double bond and two triple bonds (Compounds 12-15) . Reaction of the enediyne alcohol with chlorodiphenylphosphene forms an O-blocked allene-ene- yne phosphene oxide derivative (Compounds la, 2a, 3a and 4a. Removal of the TBS groups as with hydrogen fluoride in acetonitrile forms a desired compound (Compounds lb, 2b, 3b and 4b) . A starting halo-hydroxymethyl aromatic compound is itself typically a known compound or can be prepared by methods analogous to methods reported in the art. In one exemplary synthesis, a vicinal aromatic amino acid, 3-amino-2-naphthenoic acid, is the starting material for the formation of 3-iodo-2-naphthyl alcohol. Thus, the carboxyl group iε esterified with a convenient C 1 -C 6 alkyl alcohol such aε methanol and the ester is reduced to form the hydroxymethyl derivative. A convenient reducing arent is di-isobutylaluminum hydride (DIBAL) . Diazotization followed by reaction with an iodide salt such as KI forms the vicinal aromatic hydroxymethyliodide. Several vicinal aromatic amino acids are available commercially. For example, the Aldrich Chemical Company of Milwaukee, Wl offerε the above aminonaphthoic acid, aε well aε 2-aminonicotinic acid and 3-amino-pyrazine-2-carboxylic acid and anthranilic acid (2-aminobenzoic acid) . Aldrich Chemical also offers 2-iodobenzoic acid. In addition, several hydroxymethyl compounds are available commercially and need only be suitably halogenated for use herein. For example, all three of the hydroxymethyl pryidines, both hydroxymethyl naphthalenes and indole-3-carbinol, are also available from Aldrich, as is 2-iodobenzyl alcohol. Hydroxymethyl aromatic compounds can also be prepared from corresponding carboxylic acid esterε, as noted before. Staying with the same supplier, Aldrich Chemical Co. offerε three quinoline carboxylic acids, two indole carboxylic acids and an indole carboxaldehyde, as well as pyrazine carboxylic acid, and quinoxaline carbonyl chloride, all of which can be esterified and reduced to the corresponding hydroxymethyl compounds, then halogenated and used to form a compound of the invention. IV. Pharmaceutical Compoεitionε A compound of the invention is useful as a DNA cleaving agent, and also aε an antimicrobial (antibiotic) and a cytoxic (antitumor) agent, aε are dynamicin A, calichea icin, eεperimicin and neocarzinoεtatin. A compound of the invention can alεo therefor be referred to as an "active agent" or "active ingredient". DNA cleavage can be assayed using the techniques described hereinafter aε well as those described by Mantlo et al., J. Ore. Chem.. 54:2781 (1989); Nicolaou et al., J. Am. Chem. Soc.. 110:7147 (1989); Nicolaou et al., J. Am. Chem. Soc.. 110:7247 (1988) or Zein et al., Science. 240:1198 (1988) and the citations therein. Antimicrobial and antitumor asεayε can also be carried out by techniques described in U.S. Patent No. 4,837,206, whose disclosures are incorporated by reference, as well as by the procedures described hereinafter. A before-described compound can also be shown to undergo a Bergman cycloaromatization reaction in the presence of benzyl mercaptan, triethylamine and 1,4-cycloxadiene aε discussed in Haseltine et al., J. Am. Chem. Soc . 111:7638 (19°9) . Thiε reaction forms a tetracyclic reaction aε iε fc med during DNA cleavage, and can be used as a co-screen to select more active compounds. A pharmaceutical composition is thus contemplated that contains a before-described compound of the invention as active agent. A pharmaceutical composition is prepared by any of the methods well known in the art of pharmacy all of which involve bringing into association the active compound and the carrier therefor. For therapeutic use, a compound utilized in the present invention can be administered in the form of conventional pharmaceutical compositions. Such compositions can be formulated so as to be suitable for oral or parenteral administration, or as suppositories. In these compositions, the agent is typically dissolved or dispersed in a physiologically tolerable carrier. A carrier or diluent is a material useful for administering the active compound and must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Thus, as uεed herein, the phrases "physiologically tolerable" or "pharmaceutically acceptable" are uεed interchangeably and refer to molecular entities and co poεitions that do not produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal. The phyεiologically tolerable carrier can take a wide variety of forms depending upon the preparation deεired for ad iniεtration and the intended route of adminiεtration. Aε an example of a useful composition, a compound of the invention (active agent) can be utilized, dissolved or diεperεed in a liquid composition such as a sterile εuεpenεion or εolution, or as iεotonic preparation containing εuitable preservatives. Particularly well-εuited for the preεent purposes are injectable media conεtituted by aqueouε injectable buffered or unbuffered iεotonic and sterile saline or glucose solutions, aε well as water alone, or an aqueous ethanol . solution. Additional liquid forms in which these compoundε can be incorporated for administration include flavored emulsions with edible oils εuch as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Exemplary further liquid diluents can be found in Remminαton's Pharmaceutical Sciences, Mack Publiεhing Co., Easton, PA (1980). An active agent can also be administered in the form of liposomes. Aε iε known in the art, liposomeε are generally derived from phoεpholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are diεperεed in an aqueouε medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The preεent compositions in liposome form can contain εtabilizerε, preεervativeε, excipientε, and the like in addition to the agent. The preferred lipids are the phospholipidε and the phosphatidyl cholines (lecithinε) , both natural and synthetic. Methodε of forming lipoεo es are known in the art. See, for example, Preεcott, Ed., Methods in cell Biology. Vol. XIV, Academic press, New York, N.Y. (1976) , p.33 et seq. An active agent can also be used in compositions such as tablets or pills, preferably containing a unit dose of the compound. To this end, the agent (active ingredient) iε mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, εtearic acid, magnesium stearate, dicalci-τr. phosphate, gums, or similar materials as non-toxic, physiologically tolerable carriers. The tablets or pills can be laminated or otherwise compounded to provide unit dosage forms affording prolonged or delayed action. It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulation described herein can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidantε) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient. The tablets or pills can also be provided with an enteric layer in the form of an envelope that serves to resist disintegration in the stomach and permits the active ingredient to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including polymeric acids or mixtures of such acids with such materialε as shellac, shellac and cetyl alcohol, cellulose acetate phthalate, and the like. A particularly suitable enteric coating compriseε a εtyrene-maleic acid copolymer together with known materials that contribute to the enteric properties of the coating. Methodε for producing enteric coated tablets are described in U.S. Patent 4,079,125 to Sipos, which iε herein incorporated by reference. The term "unit dose", as used herein, refers to physically discrete units suitable aε unitary dosages for administration to warm blooded animalε, each such unit containing a predetermined quantity of the agent calculated to produce the desired therapeutic effect in association with the pharmaceutically acceptable diluent. Examples of suitable unit dosage formε in accord with thiε invention are tablets, capsuleε, pills, powder packetε, granuleε, waferε, cachetε, teaspoonfuls, dropperfuls, ampules, vialε, segregated multiples of any of the foregoing, and the like. A compound of the invention is present in such a pharmaceutical composition in an amount effective to achieve the desired result. For example, where in vitro DNA cleavage is the desired result, a compound of the invention can be utilized in an amount sufficient to provide a concentration of about 1.0 to about 5000 micromolar (μM) with a DNA concentration of about 0.02 μg/μL. As a cytoxic (antitumor) agent, an effective amount of a compound of the invention is about 0.1 to about 15 g per kilogram of body weight or an amount sufficient to provide a concentration of about 0.01 to about 50 μg/mL to the bloodstream. A compound of the invention exhibits antimicrobial activity in a concentration range of about 0.01 to about 50 μg/mL. The above concentrations and dosageε vary with the particular compound of the invention utilized aε well aε with the target, e.g., DNA, tumor, microbe, as is well known. V. Methods A compound of the invention iε useful in cleaving DNA, as an antimicrobial and also in inhibiting the growth of neoplastic cells, and is utilized in a method for effecting such a result. A compound of the invention is typically utilized in a before-described composition. In accordance with such a method, DNA or target cells to be killed or whose growth is to be inhibited are contacted with a composition that contains a compound of the invention (active ingredient) preεent in an amount effective or sufficient for such a purpose, as discussed before, dissolved or disperεed in a physiologically tolerable (pharmaceutically acceptable) diluent. That contact is maintained for a time sufficient for the desired result to be obtained; i.e., DNA cleaved, cells killed or neoplastic cell growth inhibited. Where the desired result is carried out jn vitro, contact is maintained by simply admixing the DNA or target cells with the composition and maintaining them together under the appropriate conditions of temperature and for cell growth to occur, as for control, untreated cells. Thus, a single admixing and contacting is typically sufficient for in vitro purposes. The above method iε also useful in vivo, as where a mammal such as a rodent like a rat, mouse, or rabbit, a farm animal like a horse, cow or goat, or a primate like a monkey, ape or human is treated. Here, contact of a composition and the cells to be killed or whose growth is to be inhibited is achieved by adminiεtration of the composition to the mammal by oral, nasal or anal administration or by introduction intravenously, subcutaneouεly or intraperitoneally. Thuε, contact in vivo iε achieved via the blood or lymph systems. Although a single administration (admixture) and its resulting contact is usually sufficient to maintain the required contact and obtain a desired result in vitro, multiple adminiεtrationε are typically utilized in vivo. Thuε, becauεe of a body'ε breakdown and excreting pathways, contact between an active ingredient of a composition and the target cells iε typically maintained by repeated adminiεtration of a compound of the invention over a period of time εuch aε days, weekε or onthε, or more, depending upon the target cellε. Exemplary methods of the invention for DNA cleavage and inhibition of MIA PaCa-2 human pancreatic carcinoma (ATCC CRL 1420) target cellε aε deεcribed hereinafter. VI. Reεults Compounds la,b-4a,b (Scheme 2 of Figure 2) were designed and syntheεized aε εummarized in Scheme 3 εhown in Figure 3. The key operationε involved: (a) vinyl iodide-acetylene couplingε via Pd(Cl) 2 -Cu(I) catalyεiε (step a, Scheme 3) ; (b) acetylide addition to aldehydes (step c. Scheme 3); and, (c) 2,3-sigmatropic rearrangementε (εtep d, Scheme 3) . Compoundε la, 2a and 3a were εufficiently εtable for isolation, but smoothly cyclized to aromatic syεtems, presumably via diradicalε, upon warming in the preεence of cyclohexadiene (Scheme 2, εtep a) . The half-lifes (t 1/2 ) , of theεe εystems at 37°C (la: t 1/2 -=2l hours; 2a: t 1/2 =23 hours; 3a: t 1/2 =60 hourε) indicated that they or their derivatives may be good DNA and tumor cell damaging agents with prolonged periods of action. Indeed, Compounds lb-4b exhibited DNA cleaving properties at 37°C, 42°C and 47°C in the absence of any additives. Thuε, incubation of Compoundε lb-4b (1000 μM) with supercoiled DNA (form 1) aerobically at pH 8.5 and at various temperatures caused DNA rupture leading, initially to form II and finally to form III DNA, as εhown in Figure . The anticancer activity of theεe compounds was assayed using human tumor cellε. As can be seen from Figures 5, 6 and 7 Compounds lb-4b exhibited potent, concentration-dependent cytotoxicity against human carcinoma cells thus fulfilling the initial expectations that led to the design of these εyεtems. The potency of these compounds as antitumor agents may increaεe with temperature elevation as suggeεted from the higher degree of DNA cleavage (Figure 4) , and thuε, selective tissue damage may become possible with these agents via diather ia techniques. Best Mode for Carrying out the Invention Asεay Methods DNA Cleavage Studies To a vial containing a 50 micromolar per base pair solution of 0X174 form I double-stranded DNA in 2.0 microliters of pH 8.5 phosphate buffer (50 μM) were added 6.0 microliters of the same buffer soltuion and 2.0 microliterε of a 5.0 millimolar ethanol solution of a compound to be asεayed. The vialε were then placed in an oven at the te epratureε εhown for 48 hours. A 2.0 microliter portion of glycerol loading buffer εolution containing bromothymol blue indicator waε added to each vial. A 10 microliter aliquote was then drawn from each. Gel electrophoreεis analysis of the aliquotε waε performed uεing a 2.0 percent agarose getl with ethidium bromide run at 115 volts for 1 hour. DNA cleavage waε indicated by the formation of form II or III DNA, which waε detected by visual inspection of the gel under 310 nanometer ultraviolet light. Procedure for 6-V?ell Cytotoxicity Assay MIA PaCa-2 human pancreatic carcinoma cellε were loaded into each well of a 6-well plate at a density of 100,000 cells/well in 3 ml culture medium. They were incubated for 4 hourε (37°C, 7 percent C0 2 ) . Then 6 microliters of the cytotoxin solution was added into 3 ml of medium (RPMI-1640, with 5 percent fetal bovine serum and 1 percent glutamine) in a 500X dilution so that in one well ethanol waε added to make a 0.2 percent ethanol control. The plateε were then incubated for 4 dayε (37°C, 7 percent C0 2 ) . The medium waε then drained, crystal violet dye (Hucker formula) was added to cover the well bottoms and then they were rinsed with tap water until rinses were clear. The stained cells were solubilized for quantitation with Sarkoscyl solution (N-Lauryl sarcoεine, 1 percent in water) at 3 ml/well. The abεorbance of the εolution was then read at 590-650 nm. Example 1: Compound 8 To a stirred solution of 1.93 g (10.5 mmol) of the vinyl iodide Compound 5 and 1.70 g (10.0 mmol) of the terminal alkyne (here the TBS ether of propargyl alcohol) in 20 dry benzene under argon at room temperature were added via syringe 1.54 L (15.0) mmol) of diethylamine. Immediately afterwards, 0.28 g (0.40 mmol) of bis-triphenylphoεphine palladium dichloride and 0.31 g (1.60 mmol) of cuprouε iodide were introduced aε solids. Stirring waε continued for 1 hour at room temperature. Then 30 L of saturated aqueous ammonium chloride were added, and the mixture was stirred in air for 1 hour. To this, 30 L of ether were added and the upper organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (εilica) eluting with 30 percent ether in petroleum ether to give 1.95 g of product Compound 8 in 86 percent yield. Example 2: Compound 12 To a εolution of 1.00 g (4.42 mmol) of the eyn-allylic alcohol Compound 8 in 20 mL of dry benzene at room temperature were added 7.00 g (80.5 mmol) of activated manganese dioxide and the mixture waε stirred at room temperature for 24 hours. The mixture waε filtered through celite, and the filter cake waε waεhed with 60 mL of tetrahydrofuran. The filtrateε were concentrated to give 0.84 g of the aldehyde in 84 percent yield. 6.13 milliliters (9.84 mmol) of 1.6M n- butyllithium in hexanes were added by syringe to a stirred solution of 1.97 g (11.59 mmol) of the t-butyldimethylsilyl (TBS) ether of propargyl alcohol in 40 L tetrahydrofuran under an argon atmosphere cooled to -78°C. Stirring was continued for 30 minutes, while allowing the temperature to rise to -10°C. The reaction mixture was cooled to -20°C and a solution of 2.00 g (8.91 mmol) of the aldehyde i.. 10 mL of tetrahydrofuran was added dropwise by syringe over 5 minutes. After stirring for 1 hour, 100 mL of saturated aqueous ammonium chloride and 50 L of ether was added. The upper organic layer was dried over magneεium εulfate, filtered, and concentrated. The reεidue waε purified by flash chromatography (silica) eluting with 25 percent ether alcohol in petroleum ether to give 3.48 g of product ene-diyne alcohol Compound 12 in 99 percent yield. Pale yellow oil; R f - 0.48 (silica, 30 percent ether in petroleum ether) ; 1 H NMR (500 MHz, CDC1 3 ) δ 5.98 (dd, J=10.6, 8.8 Hz, 1 H, =CH-CHOH) , 5.65 (dt, J=10.6, 2.0 Hz, 1 H, ≡C-CH=CH) , 5.41 (bd, J=8.8 Hz, 1 H, =CH=CHOH) , 4.46 (bd, J=2.0 Hz, 2 H, CH 2 0) , 4.35 (d, J=1.8 Hz, 2 H, CH 2 0) , 0.91 (ε, 9 H, Si r BuMe 2 ) , 0.90 (ε, 9 H Si r BuMe 2 ) , 0.13 (ε, 6 H, S^BuMe.,) , 0.11 (ε, 6 H, Si t BuMe 2 ) , IR (CHC1 3 ) V mχ 3596, 2957, 2931, 2859, 1472, 1364, 1257, 1128, 1077, 838 cm "1 ; 3 C NMR (125 MHz, CDC1 3 δ 140.4 (=CH-CHOH) , 111.0 (≡CH-CHOH) , 52.1 (CH ∑ 0) , 51.7 (CH 2 0) , 25.8 (Si r BuMe 2 ) , 18.2 (S^Bu e j ) , - 5.2 (Si t BuMe 2 ) ; UV (EtOH) λ^ 230 nm (e 11,500). Example 3: Compound la To a εtirred εolution of 1.00 g (2.53 mmol) of the ene-diyne alcohol in 35 L of dry methylene chloride, cooled to -78°C, were added via syringe 0.39 L (2.79 mmol) of triethylamine followed by 0.50 L (2.79 mmol) chlorodiphenylphosphine. Stirring waε continued for 1 hour and 50 L of εaturated aqueous ammonium chloride were added. The lower organic layer waε dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica) eluting with 80 percent ether in petroleum ether to give 1.23 g of the phoεphine oxide Compound la in 84 percent yield. Pale yellow oil, R f = 0.40 (silica, ether) ; 1 H NMR (500 MHz, CDClD j ) δ 7.78-7.67 (m, 4 H, aromatic), 7.53-7.40 (m, 6 H, aromatic), 6.43 (ddtd, J * =10.7, 10.7, 2.7, 1.0 Hz, 1 H, CH=C=) , 6.03 (ddd, J=10.7, 10.7, 1.8 Hz, 1 H, CH=CH-CH=) , 5.35 (dm,J=10.7 Hz, 1 H, 2 H, -EC-CH 2 0) , 0.90 (S, 9 H, Si l BuMe 2 ) , 0.79 (s, 9 H, Si T BuMe 2 ) , 0.11 (s, 3 H, Si r BuMe 2 ) , 0.10 (s, 3 H, Si t BuMe 2 ) , -0.03 (s, 6 H, Si τ BuMe 2 ) ; IR (CHC1 3 ) v^ 2957, 2931, 2858, 1931, 1603, 1471, 1438, 1258, 1171, 1119, 1098, 839 cm "1 ; 13 C NMR (125 MHz, CDCl j ) δ 212.4 ( 2 Jccp=4.4 Hz, CH=C*=C) , 132.8-128.1 (thirteen overlapping signals, aromatic, -≡C-CH=) , 109.7 ( 4 Jccccp=4.9 Hz, C=CH-CH=) , 101.8 ( 1 Jcp=98.5 Hz, CH=C=C) , 95.6 (acetylene) , 94.9 ( 3 Jcccp=13.0 Hz, CH=C=C) , 80.7 (acetylene), 60.3 ( 2 Jccp=10.5 Hz, =C(P=0)-CH 2 0) , 52.1 (εC-CH 2 0) , 25.7 (Si t BuMe 2 ) , 25.6 , 18.1 (Si t BuMe 2 ) , -5.2 (Si t BuMe 2 ) , -5.6 (Si t BuMe 2 ) ; UV (EtOH) λ^ 274 (e 10,500), 267 (e 10,500) , 222 nm (e 28,000) ; HRMS calcd for C 33 H 4S 0 3 PSi 2 (MΦ+1) : 579.2879, found: 579.2877. Example 4: Compound lb 0.10 Milliliters of 48 percent aqueous hydrofluoric acid were added to a solution of 34.7 mg (0.0599 mmol) of the phosphine oxide Compound la in 1.0 mL of acetonitrile at room temperature. After stirring for 15 minuteε, the solvents were pumped off at 0.01 torr. The residue waε dissolved in 1.0 mL of chloroform and the solvent waε again pumped off to give 20.2 mg of the diol in Compound lb in 96 percent yield. Pale yellow oil, R f = 0.27 (silica, ethyl acetate); 1 H NMR (500 MHz, CDC1 3 ) δ 7.77-7.40 (m, 10 H, aromatic), 6.08 (dd, J=10.4, 10.4 Hz, 1 H, CH=C=) , 5.77 (dd, J=10.4, 10.4 Hz, 1 H, • =CH.-CH=C=) , 5.52 (dm, J=10.4 HZ, 1 H, , 4.44 (m, 4 H, -CH. 2 OH) , 3.4 (bs, 2 H, OH); IR (neat) v^ 3318, 2971, 2950, 2871, 1928, 1438, 1169, 1120 cm "1 ; UV (EtOH) λ^ 274 (e 18,500), 222 n (sh, e 26,500); HRMS calcd for C 21 H 19 0 3 PCs (M®+Cε) : 483.0126, found: 483.0126. Example 5: Compound 16a A εolution of 123 mg (0.212 mmol) of the ene- yne-allene Compound la in 5.0 mL of 1,4-cyclohexadiene was stirred at 37°C for 35 hours and then concentrated. Preparative TLC (εilica, 0.5 u x 20 x 20 cm) eluting with 80 percent ether in petroleum ether gave 74 mg of the cyclized product Compound 16a in 60 percent yield. Pale yellow oil, R f = 0.43 (εilica, ethyl acetate); 1 H NMR (500 MHz, CDC1 3 ) δ 7.97 (dd, 3=1.1 , 1.6 Hz, 1 H, aromatic), 7.94 (dd, J=7.8, 1.6 Hz, 1 H, aromatic), 7.84 (d, J=7.4 Hz, 1 H, aromatic), 7.58-7.50 (m, 5 H, aromatic), 7.28 (m, l H, aromatic), 7.21-7.13 (m, 5 H, aromatic), 4.75 (d, J= 12.0 Hz, 1 H, Ar-CH 2 0) , 4.57 (d, J=12.0 Hz, 1 H, Ar-CH 2 0) , 4.34 (m, 2 H, Ar-CH(P=0), CH-CH 2 0) , 4.14 (m, I H, CH-CH 2 0) , 1.01 (ε, 9 H, S^BuMe j ) , 0.69 (ε, 9 H, S^BuMe.,) , 0.17, 0.16, -0.20, -0.26 (εingletε, 3 H each, S^Bu e j ) ; IR (CHC1 3 ) v naχ 2957, 2930, 2858, 1471, 1438, 1257, 1117, 1101, 838 cm '1 ; 13 C NMR (125 MHz, CDC13) δ 139.1-126.9 (εeveral εignalε, aromatic), 64.7 (CH 2 0) , 64.3 (CH 2 0) , 43.9 ( 1 Jcp=67.9 Hz, Ar-CH(P=0), 26.1 (Si r BuMe 2 ) , 25.7 (Si t BuMe z ) , 18.6 (Si t BuMe 2 ) , 18.1 (Si t BuMe 2 ) , -5.1, -5.2, -5.8, -5.9 (Si l BuMe 2 ) ; UV (EtOH) λ^ 266 nm (e 3,500); HRMS calcd for C 33 H 50 O 3 PSi 2 (MΦ+1) : 581.3036, found: 581.3012. Example 6: Compound 16b 0.10 Milliliterε of 48 percent aqueouε hydrofluoric acid were added to a εolution of 112 mg (0.193 mmol) of the cyclized product Compound 16a in 1.0 mL of acetonitrile at room temperature. After stirring for 15 minutes, the solventε were pumped off at 0.01 torr. The reεidue waε dissolved in 1.0 mL of chloroform and the solvent waε again pumped off to give 68 mg of the diol in Compound 16b in quantitative yield. Compound 6 was purchased from Aldrich Chemical Co., Milwaukee, WI. Compounds 9, 13, 2a, 2b and 17a were prepared in annerε substantially similar to the methodε utilized for preparing Compoundε 8, 12, la, lb and 16a. Data relating to Compoundε 13, 2a, 2b and 17a are provided below. Compound 13 Pale yellow oil, R f = 0.50 (εilica, 30 percent ether in petroleum ether); 1 H NMR (300 MHz, CDC1 3 ) £ 7.70 (d, J=7.7 Hz, 1 H, aromatic), 7.45-7.27 ( , 3 H, aromatic), 5.91 (bε, 1 H, CHOH), 4.59 (ε, 2 H, Ar-C≡C-CH 2 0) , 4.40 (d, J=1.6 Hz, 2 K, CH0H-C≡C-CK 2 0) , 2.58 (bε, 1 H, OH), 0.95 (ε, 9 H, Si τ BuMe 2 ) , 0.90 (ε, 9 H, Si t BuMe 2 ) , 0.18 (ε, 6 H, Si τ BuMe 2 ) , 0.11 (ε, 6 H, S^Bu e j ) ; IR (CHC1 3 ) V Blχ 3595, 2957, 2931, 2859, 1472, 1365, 1256, 1079, 838 cm '1 ; 13 C NMR (125 MHz, CDCl 3 ) £ 142.1 (aromatic), 132.5 (aromatic), 128.8 (aromatic), 128.2 (aromatic) , 126.7 (aromatic), 121.1 (aromatic) , 93.2 (acetylene), 85.3 (acetylene) , 83.8 (acetylene) , 82.0 (acetylene), 62.9 (CHOH), 52.2 (CH 2 0) , 51.8 (CH 2 0) , 25.8 (Si t BuMe 2 ) , 18.3 (Si t BuMe 2 ) , 18.2 (Si r BuMe 2 ) , -5.1 (Si l BuMe 2 ) , -5.2 (Si t BuMe 2 ) ; UV (EtOH) λ^ 244 (e 13,000) , 209 n (e 28,000) . Compound 2a Pale yellow oil, R = 0.40 (silica, ether) ; 1 H NMR (300 MHz, CDC1 3 ) δ 7.97-7.81 (m, 4 H, aromatic), 7.66-7.39 ( , 8 H, aromatic), 7.30-7.21 (m, 2 H, aromatic) , 6.91 (dt, J=10.6, 2.9 Hz, 1 H, CH=C=) , 4.72 (n, 2 H, =C(P=0)-CH 2 0) , 4.66 (s, 2 H, sC-CH 2 0) , 1.06 (s, 9 K, Si x BuMe 2 ) , 0.90 (ε, 9 K, Si'Bu e^ , 0.27 (ε, 6 H, Si : BuMe 2 ) , 0.09 (ε, 6 K, Si : BuMe 2 ) ; IR (CHC1 3 ) RBχ 295E, 2931, 2858, 1938, 1487, 1438, 1363, 1256, 1181, 112C, 1098, 838 cm "1 ; 13 C NMR (125 MHz, CDC13) δ 210.3 ( 2 Jccp=5.3 Hz, CH=C=C) , 133.9 ( 4 Jccccp=6.8 Hz, aromatic), 132.5-120.7 (sixteen εignals, aromatic), 103.8 ( 1 Jcp=99.2 HZ, CH=C=C) , 96.2 ( 3 Jcccp=12.9 Hz, CH=C=C) , 92.8 (acetylene) , 82.4 (acetylene) , 60.5 ( 2 Jccp= 10.8 Hz, =C(P=0)-CH 2 0) , 52.2 (s * C-CH 2 0) , 25.8 (Si t BuMe 2 ) , 25.7 (Si*BuMe 2 ) , 18.3 (S^BuMe j ) , 18.2 (Si t BuMe 2 ) , -5.1 (Si t BuMe 2 ) , -5.5 (Si t BuMe 2 ) ; UV (EtOH) A *r«x 274 ( € 23,000), 223 nm (e 37,000) ; HRMS calcd for C 37 H 50 O 3 PSi 2 (MΦ+1) : 629.3036, found: 629.3081. Compound 2b Pale yellow oil, R - 0.27 (εilica, ethyl acetate); 1 H NMR (500 MHz, CDC1 3 ) δ 7.82 (m, 2 H, aromatic), 7.67 (m, 2 H, aromatic), 7.58 (m, 1 H, aromatic), 7.52 (m, 2 H, aromatic), 7.37 (m, 2 H, aromatic), 7.26 (m, 2 H, aromatic), 7.14 (m, 2 H, aromatic), 6.89 (m, 1 H, aromatic), 6.33 (dt, J=10.8, 2.2 Hz, 1 H, CH=C=) , 4.59 (d, J=16.7 Hz, 1 H, sC-CH 2 0) , 4.50 (d, J=16.7 Hz, 1 H, ≡C-CH 2 0) , 4.49 (m, 2 H, =C(P=0)-CH 2 0) ; IR (CHC1 3 ) V Mχ 3307, 3011, 2929, 2856, 1936, 1438, 1220, 1160, 1120, 1028 cm '1 ; 13 C NMR (125 MHZ, CDCl j ) δ 211.1 ( 2 Jccp=5.9 Hz, CH=C=C) , 134.0-127.6 (fifteen signals, aromatic), 121.4 (aromatic), 101.4 ( 1 Jcp=99.2 HZ, CH=C=C) , 96.6 ( 3 Jcccp=13.1 Hz, CH=C=C) , 95.8 (acetylene), 83.5 (acetylene), 61.2 ( 2 Jccp=7.2 Hz, =C(P=0)-CH 2 OH) , 51.4 (≡C-CH 2 OH) ; UV (EtOH) λ |Mχ 267 (sh, € 7,200), 226 nm (e 31,000) ; HRMS calcd for C 25 H 21 0 3 PCε (MΦ+Cε) : 533.0282, found: 533.0274. Compound 17a Pale yellow oil, R f = 0.44 (εilica, ethyl acetate); H NMR (500 MHz, CDC1 3 ) δ 8.30 (bε, 1 H, aromatic), 7.94 (m, 2 H, aromatic), 7.80 (m, 1 H, aromatic), 7.72 (m, 1 H, aromatic), 7.64 (s, 1 H, aromatic), 7.52 (m, 5 H, aromatic), 7.40 (m, 2 H, aromatic), 7.18 (r., 1 K, aromatic), 7.10 (m, 2 K, aromatic), 4.87 (d, J=12.1 Hz, 1 K, Ar-CH ∑ 0) , 4.72 (d, J=12.1 Hz, 1 H, Ar-CH 2 0) , 4.43 (m, 2 K, Ar-CH(P=0), CH-CH 2 0) , 4.20 ( , 1 H, CH-CH ∑ 0) , 1.00 (£, 9 H, Si t BuMe 2 ) , 0.64 (ε, 9 H, Si τ BuMe 2 ) , 0.18, 0.16, -0.25, -0.32 (singlets, 3 H each, S^BuMe.,) ; IR (CHC1 3 ) v^ 2957, 2930, 2858, 1471, 1438, 1258, 1220, 1097, 839 cm "1 ; 13 C NMR (125 MHz, CDC1 3 ) 6 137.2-125.7 (several signals, aromatic), 65.3 (CH 2 0) , 64.8 (CH 2 0) , 43.6 ( 1 Jcp=67.9 Hz, Ar-CH(P=0)), 26.1 (S^BuMe^ , 25.7 (Si : BuMe 2 ) , 18.7 (Si : BuMe 2 ) , 16.1 (Si t BuMe ∑ ) , -5.1, -5.1, -5.B, -5.9 (Si τ BuMe 2 ) ; UV (EtOH) λ^ 233 nm (e 50,000); HRMS calcd for C 3 ,H 52 0 3 PSi 2 (M**-*l) : 631.3192, found: 631.3157. Example 7: 3-Iodo-2-naththyl Alcc l fCcrrour.d 7) To 500 ml of methanol (MeOH) and 50 r.l of acetyl chloride were added 11.950 g (63.83 mmol) of 3-amino-2-naphthoic acid in 100 ml of MeOH. To this mixture were added 50 ml of benzene and 50 ml of CH 2 C1 2 and the reaction waε stirred at room temperature for two hours and then at reflux for three hours. Then MgS0 6 was added and the reaction was heated at reflux for 12 hours. The MgSO^ was replaced with 3λ molecular sieves, and the reaction mixture was heated to reflux for 48 hours. The reaction mixture waε then diluted with 500 ml of ethyl acetate (EtOAC) , waεhed with 100 ml of εaturated NH 4 C1, 100 ml of εaturated NaHC0 3 , 100 ml of 5 percent Na 2 C0 3 , brine, dried over MgS0 ώ and concentrated. The product waε purified by column chromatography (10 percent ether in petroleum ether) to give 7.412 g (36.82 mmol) of the aminonaphthoic ester (56 percent yield) . To 0.500 g (2.500 mmol) cf the above ester in 25 ml cf CH,C1 2 were added 10 r.l cf DIBAL (1 M in hexaneε) at -78 C C, and the reaction mixture was warmed to room temperature. To the reaction mixture were added 20 mi cf MeOH, 50 ml of EtOAC and 20 ml of Rochelle's εalt. The organic layer waε washed with εaturated ammonium chloride, dried over MgS0 4 and concentrated. The product was recrystallized from toluene to yield 0.255 g (1.472 mmol) of 3-amino-2-naphthyl alcohol (5S percent yield) . The above a inonaphthyl alcohol (1.340 g; 7.736 mmol) in 13 ml of 6M εulfuric acid waε heated to form a εolution and then cooled to zero degrees C. T the resulting εuεpenεion were added 0.587 g (8.510 mmol) cf NaN0 2 in 2 ml of water, and the reaction mixture was stirred at zero degreeε C for 10 minutes. Then, 0.2C0 g of urea in 2 ml of water were added at zero degrees C, with εtirring for 5 minutes, followed by 1.926 g (11.604 mmol) of KI in 2 ml of water at zero degreeε C with εtirring at room temperature for 15 minutes. A 50 ml portion of 1:1 ether-ethyl acetate, and 20 ml of εaturated ammonium chloride and 20 ml of sodium biεulfate were added, the organic layer waε εeparated and waεhed with ammonium chloride, sodium bicarbonate and brine, and then dried over MgS0 4 . The product was purified by column chromatography (30 percent ether in petroleum ether) to give 0.585 g (27 percent yield) cf 3-iodo-2-naphthyl alcohol. Compounds 10, 14, 3a, 3b and 18a were prepared analogously to Compoundε 8, 12, la, 16 and 16a uεing 3- iodo-2-naphthyl alcohol, Compound 7, in place of Compound 5. Data relating to Compoundε 14, 3a, 3b and 18a are provided below. Compound 14 Pale yellow oil; R,- = 0.64 (εilica, 60 percent ether in petroleum ether); ' Ε NMR (500 MHz, CDC1 3 ) £ 8.15 (s, 1 K, aromatic), 7.99 (ε, 1 K, aromatic), 7.62 ( , 1 H, aromatic), 7.77 ( , 1 H, aromatic), 7.50 (m, 2 H, aromatic), 6.01 (ε, 1 H, CHOH), 4.63 (ε, 2 H, Ar-CsC-CH 2 0) , 4.44 (bs, 2 H, CHOH-CsC-Cfi 2 0) , 2.85 (bε, 1 H, CHOH), 0.97 (s, 9 H, Si t BuMe 2 ) , 0.91 (ε, 9 H, Si r BuMe 2 ) , 0.20 (s, 6 H, Si t BuMe 2 ) , 0.13 (s f 3 H, ; IR (CHCl 3 ) v mχ 3592, 2960, 2931, 2859, 1472, 1368, 1257, 1101, 1078, 838 cm '1 ; 13 C NMR (125 MHZ, CDCl 3 ) δ 138.3 (aromatic), 133.0 (aromatic), 132.8 (aromatic), 132.6 (aromatic), 128.1 (aromatic), 127.4 (aromatic), 127.1 (aromatic), 126.9 (aromatic), 126.1 (aromatic), 118.7 (aromatic), 92.8 (acetylene), 85.6 (acetylene), 83.8 (acetylene), 82.4 (acetylene), 63.2 (CHOH), 52.3 (CH 2 0) , 51.9 (CH 2 0) , 25.8 (Si t BuMe 2 ) , 18.3 (Si t BuMe 2 ) , 18.3 (Si r BuMe 2 ) , -5.1 (Si t BuMe 2 ) , -5.1 (Si*BuMe 2 ) ; UV (EtOH) λ^ 278 (e 6,900), 250 (e 54,500), 241 nm (e 44,000). Compound 3a Pale yellow oil; R f = 0.48 (silica, ether); 1 H NMR (500 MHz, CDC1 3 ) δ 7.87 (s, 1 H, aromatic), 7.86- 7.76 (m, 4 H, aromatic), 7.71 (d, J=7.9 Hz, 1 H, aromatic), 7.64 (d, J=7.6 Hz, 1 H, aromatic), 7.52 (m, 2 H, aromatic), 7.44 (m, 4 H, aromatic), 7.34 (m, 1 H, aromatic), 7.28 (m, 2 H, aromatic), 6.89 (dt, J=10.7, 2.9 Hz, 1 H, CH=C=) , 4.66 (m, 2 H, -C(P-O)-CH ∑ 0) , 4.58 (s, 2 H, =C-CH 2 0) , 0.96 (s, 9 H, Si t B;iMe 2 ) , 0.79 (s, 9 H, SitBuMe2), 0.18 (s, 3 H, SitBuMe2) , 0.17 (s, 3 H, Si t BuMe 2 ), -0.02 (s, 6 H, Si t BuMe 2 ) ; IR (CHC1 3 ) v^ 2957, 2_ .l, 2858, 1939, 1472, 1438, 1364, 1257, 1181, 1105, 1086, 838 cm '1 ; 13 C NMR (125 MHz, CDC1 3 ) d 210.4 ( 2 Jccρ=5.1 Hz, CH=C=C) , 132.8-119.0 (twenty-two signals, aromatic), 103.6 ( 1 Jcp=99.3 Hz, CH=C*=C , 96.2 ( 3 Jcccp=13.1 Hz, CH=C=C) , 92.4 (acetylene), 82.6 (acetylene) , 60.6 ( 2 Jccp= 10.6 Hz, =C(P=0)-CH 2 0) , 52.3 (=C-CH 2 0) , 25.8 (Si t BuMe 2 ) , 25.7 (Si t BuMe 2 ) , 18.3 (Si t BuMe 2 ) , 18 . 2 (Si t BuMe 2 ) , -5 . 0 (S^BuMe j ) , -5. 5 (Si t BuMe 2 ) -5 . 5 (S^BuMe j ) ; UV (EtOH) λ^ 267 ( e 57 , 000 ) , 226 nm ( e 38 , 000 ) ; HRMS calcd for C 1 H 52 0 3 PSi 2 (M©+1 ) : 679 . 3192 , found : 679 . 3169 . Compound 3b Pale yellow oil, R f - 0.28 (εilica, ethyl acetate); 1 H NMR (500 MHz, CDC1 3 ) <S 7.86 (ε, 1 H, aromatic), 7.80 (m, 2 H, aromatic), 7.66 (m, 3 H, aromatic), 7.59-7.47 (m, 4 H, aromatic) , 7.37 (m, 2 H, aromatic, 7.27 (ε, 1 H, aromatic), 7.25-7.16 (m, 3 H, aromatic), 6.42 (bd, J=10.6 Hz, 1 H, CH=C=) , 4.59 (d, J=16.7 HZ, 1 H, ≡C-CH 2 0H) , 4.51 (m, 2 H, =C(P=0)-CH 2 OH) , 4.49 (d, J=16.7 Hz, 1 H, εC-CH 2 OH) ; IR (CHC1 3 ) V^ 3349, 3011, 2961, 2930, 2857, 1936, 1438, 1214, 1120, 1099, 1028 cm "1 ; 13 C NMR (125 MHz, CDCl 3 ) .5 211.2 (CH=C=C) , 134.3-119.0 (fifteen εignalε, aromatic), 101.4 ( 1 Jcp=97.6 HZ, CH=C=C) , 96.9 ( 3 Jcccp=12.9 Hz, CH=C=C) , 94.7 (acetylene), 83.6 (acetylene) , 61.1 ( Jccp=7.1 Hz, =C(P=0)-CH 2 OH) , 51.4 (≡C-£H 2 OH) ; UV (EtOH) λ^ 266 (e 46,000), 224 nm (εh, e 22,000) ; HRMS calcd for C 2 H 23 ° 3 PCs (MΦ+Cε) : 583.0438, found: 583.0471. Compound 18a Pale yellow oil, R f = 0.51 (silica, ethyl acetate) ; "H NMR (500 MHz, CDC1 3 ) δ 8.46 (d, J=1.8 Hz, 1 H, aromatic), 8.37 (ε, 1 H, aromatic), 8.28 (ε, 1 H, aromatic), 7.94 (m, 4 H, aromatic), 7.79 (s, 1 H, aromatic), 7.52 (m, 5 H, aromatic), 7.41 (m, 2 H, aromatic), 7.14 (m, 1 H, aromatic), 7.06 (m, 2 H, aromatic), 4.89 (d, J=12.3 Hz, 1 H, Ar-CH 2 0) , 4.74 (d, J=12.3 HZ, 1 H, Ar-CH 2 0) , 4.44 (m, 2 H, Ar-CH(P=0) , CH- CH 2 0) , 4.23 (m, 1 H, CH-CH 2 0) , 1.00 (ε, 9 H, Si r BuMe 2 ) , 0.63 (ε, 9 H, Si : BuMe 2 ) , 0.17, 0.16, -0.26, -0.34 (εingletε, 3 H each, Si t BuMe 2 ) ; IR (CHC1 3 ) v (nBX 2957, 2925, 2857, 1471, 1438, 1256, 1117, 1097, 839 cm "1 ; 13 C NMR (125 MHz, CDC1 3 ) δ 137.0-125.2 (εeveral signals, aromatic) , 65.4 (CH 2 0) , 65.0 (CH 2 0) , 43.6 ( 1 Jcp= 67.9 Hz, Ar-CH(P=0)) , 26.2 (Si t BuMe 2 ) , 25.7 (Si t BuMe 2 ) , 18.7 (Si t BuMe 2 ) , 18.1 (Si r BuMe 2 ) , -5.0, -5.1, -5.8, -5.9 (Si t BuMe 2 ) ; UV (EtOH) λ mχ 381 (e 8,600), 263 nm (e 81,000) ; HRMS calcd for C 41 H w 0 3 PSi 2 (M*+l) : 681.3349, found: 681.3356. Compounds 11, 15, 4a and 4b were prepared in a manner analogouε to the preparation of Compoundε 8, 12, la and lb except that Compound 5 was reacted with phenylacetylene instead cf the TBS-protected propargyl alcohol. Data relating to Compoundε 15, 4a and 4b are provided below. Compound 15 Pale yellow oil, R f = 0.45 (εilica, 30 percent ether in petroleum ether); 1 H NMR (500 MHz, CDC1 3 ) £ 7.43 (m, 2 H, aromatic), 7.31 (m, 3 H, aromatic), 6.03 (dd, J=10.7, 8.9 HZ, 1 H, =CH-CHOH) , 5.83 (d, J-10.7 Hz, 1 H, sC-CH=CH) , 5.51 (m, 1 H, -=CH-CH.OH) , 4.35 (d, J= 0.S Hz, 2 H, CH 2 0) , 2.16 (d, J= 4.3 Hz, 1 H, CHOH) , 0.88 (ε, 9 H, Si t BuMe 2 ) , 0.10 (ε, 6 H, Si : BuMe 2 ) ; IR (CHC1 3 ) 8,2? n m β x 35 * ? * 3 » 2957, 2931, 2855, 1490, 1472, 1257, 1131, 1077, 838 cm '1 ; 13 C NMR (125 MHz, CDC13) <5 140.1 (C=CH-CHOH) , 131.6 (aromatic), 128.6 (aromatic) , 128.3 (aromatic) , 122.7 (aromatic) , 111.5 (CH=C-CHOH) , 96.0 (acetylene) , 84.5 (acetylene) , 84.2 (acetylene) , 83.5 (acetylene) , 60.3 (CHOH) , 51.6 (CH 2 0) , 25.8 (Si t BuKe 2 ) , 18.2 (Si r BuMe 2 ) , -5.1 (Si T BuMe 2 ) ; UV (EtOH) λ Mχ 291 (e 12,500) , 275 nr. (e 15,000) . Compound 4a Pale yellow oil, R f = 0.40 (εilica, ether) ; 1 H NMR (500 MHz, CDC1 3 ) δ 7.90 ( , 1 H, aromatic), 7.78- 7.68 ( , 4 H, aromatic), 7.52-7.35 (m, 8 H, aromatic), 7.29 ( , 2 H, aromatic), 6.53 (dddd, J=10.7, 10.7, 2.7, 2.1 HZ, 1 H, CH=C=) , 6.09 (ddd, J=10.7, 10.7, 1.8 Hz, 1 H, CH=CH-CH=) , 5.54 (bdd, J=10.7, 3.0 Hz, 1 H, ≡C-CH=CH) , 4.49 (m, 2 H, CH 2 0) , 0.79 (ε, 9 H, S^Bu e j ) , -0.04 (ε, 6 H, S^BuMe j ) ; IR (CHC1 3 ) v Mχ 2988, 2958, 2931, 2851, 1930, 1592, 1438, 1182, 1120, 1103, 838 cm '1 ; 13 C NMR (125 MHz, CDCl 3 ) <5 212.6 ( 2 Jccp= 4.4 Hz, CH=C=C) , 132.6-128.3 (εeveral εignalε, aromatic, ≡C-CH=) , 123.0 (aromatic), 110.2 ( 4 Jccccp=4.8 Hz, CH=CH-CH=) , 102.0 ( 1 Jcp=98.0 Hz, CH=C=C) , 97.2 (acetylene), 95.3 ( 3 Jcccp=13.0 Hz, CH=C=C) , 85.6 (acetylene), 60.5 ( 2 Jccp=10.6 Hz, CH 2 0) , 25.7 (Si t BuMe 2 ) , 18.2 (Si t BuMe 2 ) , -5.4 (Si l BuMe 2 ) , -5.5 (S^BuMe j ) ; UV (EtOH) λ Mχ 328 (e 17,000), 309 (e 23,000), 222 n (εh, e 17,000); HRMS calcd for C 32 H 6 0 2 PSi (MΦ+1) : 511.2222, found: 511.2230. Compound 4b Pale yellow oil, R = 0.32 (εilica, ethyl acetate); H NMR (500 MHz, CDC13) δ 7.80-7.68 (m, 4 H, aromatic), 7.56-7.43 (m, 6 H, aromatic), 7.38 ( , 2 H, aromatic), 7.31 (m, 3 H, aromatic), 6.52 (bdd, J=10.7, 10.7 Hz, 1 H, CH=C=) , 6.07 (ddd, J=10.7, 10.7, 1.8 Hz, 1 H, CH=CH-CH=) , 5.59 (dd, J=10.7, 2.9 Hz, 1 H, sC-CH=CH) , 4.50 (m, 2 H, CH 2 0) ; IR (CHC1 3 ) V^ 3360, 3020, 1929, 1592, 1490, 1439, 1210, 1168, 1121, 1070, 775 cm-1; 13 C NMR (125 MHz, CDC1 3 ) δ 213.5 (CH=C=C) , 134.1-128.3 (eeveral overlapping signalε, aromatic, sc-CH=) , 122.7 (aromatic) , 111.3 (C=CH-CH=) , 99.2 (CH=C=C) , 97.7 (acetylene) , 94.9 ( 3 Jcccp=12.6 Hz, CH=C=C) , 85.4 (acetylene), 60.7 (CH 2 OH) ; UV (EtOH) λ x 307 (e 14,000), 223 nm (εh, e 18,000) ; HRMS calcd for C 26 H 22 0 2 P (MΦ+1) : 397.1357, found: 397.1376. Although the present invention has now been described in terms of certain preferred embodiments, and exemplified with respect thereto, one skilled in the art will readily appreciate that various modifications, changes, omiεεionε and εubεtitutions may be made without departing from the spirit thereof.

Claims: CLAIMS: 1. A diphenyl-(l,8-disubstituted-octa-2,3,5- trien-7-yne)phoεphene oxide. 2. The phosphene oxide according to claim 1 wherein the 1- and 8-poεition substituents are selected from the group consiεting of hydroxyl, hydroxymethyl, phenyl and C 1 -C 6 acyloxy. 3. The phosphene oxide according to claim 2 wherein the 5-position double bond iε shared with an aromatic ring εyεtem that containε one or two fused rings. 4. The phosphene oxide according to claim 1 wherein said aromatic ring εyεtem iε εelected from the group conεiεting of a subεtituted or unεubεtituted benzene, naphthalene, pyridine, quinoline, isoguinoline, pyrazine, quinoxaline, benzofuran, furan, thiophene, oxazole, pyrimidine, benzothiophene, isobenzofuran, isobenzothiophene, N-C,-C 6 alkyl indole, N-C 1 -C 6 alkyl isoindole, N-C 1 -C 6 alkyl benzimidazole, and benzoxazole. 5. The phoεphene oxide according to claim 2 wherein said aromatic ring system is benzene or naphthalene. 6. 2-Diphenylphosphoroεo-nona-2,3,5-trien-7- yne-l,9-diol. 7. 2-Diphenylphoεphoroεo-8-phenyl-octa- 2,3,5-trien-7-yn-l-ol. 8. 1-(3-Diphenylphoεphoroεo-3-hydroxy-prop- 1,2-dienyl)-2-(3-hydroxy-prop-1-ynyl)benzene. 9. 2-(3-Diphenylphoεphoroso-3-hydroxy-prop- 1,2-dienyl)-3-(3-hydroxy-prop-l-ynyl)naphthalene. 10. A pharmaceutical compoεition compriεing a pharmaceutically effective amount of a diphenyl-(1,8- disubstituted-octa-2 ,3,5-trien-7-yne)phoεphene oxide diεpersed in a physiologically tolerable diluent. 11. The pharmaceutical compoεition according to claim 10 wherein the 1- and 8-poεition substituentε are selected from the group consisting of hydroxyl, hydroxylmethyl, phenyl and C 1 -C 6 acyloxy. 12. The pharmaceutical composition according to claim 11 wherein the 5-position double bond iε εhared with an aromatic ring system that contains one or two fused rings. 13. The pharmaceutical composition according to claim 10 wherein said aromatic ring system is selected from the group conεisting of benzene, naphthalene, pyridine, guinoline, isoguinoline, pyrazine, quinoxaline, benzofuran, furan, thiophene, oxazole, pyrimidine, benzothiophene, isobenzofuran, iεobenzothiophene, N-C,-C 6 alkyl indole, N-C 1 -C 6 alkyl iεoindole, N-C 1 -C 6 alkyl benzimidazole, and benzoxazole. 14. The pharmaceutical compoεition according to claim 11 wherein said aromatic ring system iε benzene or naphthalene. 15. The pharmaceutical compoεition according to claim 10 wherein the phoεphene oxide iε selected from the group consisting of 2-diphenylphosphoroεo-nona- 2,3,5-trien-7-yne-l,9-diol, 2-diphenylphoεphoroεo-8- phenyl-2,3,5-trien-7-yn-l-ol, l-(3-diphenylphoεphoroεo- 4-hydroxy-prop-1,2-dienyl)-2-(3-hydroxy-prop-l- ynyl)benzene and 2-(3-diphenylphoεphoroεo-3-hydroxy- prop-1,2-dienyl)-3-(3-hydroxy-prop-1-ynyl)naphthalene. 16. A method of cleaving DNA that comprises contacting DNA with a compoεition that containε an effective amount of an active agent that iε a diphenyl- (1,8-diεubstituted-octa-2,3-5-trien-7-ybne)phoεphene oxide disεolved or diεperεed in a phyεiologically tolerable diluent, and maintaining εaid contact for a time period sufficient for εaid DNA to be cleaved. 17. The method according to claim 16 wherein εaid active agent haε εtructure that corresponds to the formula wherein Ph iε phenyl; R 1 and R 2 are hydrogen or R 1 and R 2 together with the unεaturated carbon atomε bonded thereto form a mono- or bicyclic aromatic ring; R 3 iε hydroxyl or C 1 -C 6 acyloxy; and R 4 iε hydroxymethyl, C,-C 6 acyl hydroxymethyl or phenyl. 18. The method according to claim 16 wherein εaid active agent iε εelected from the group consiεting of 2-diphenylphoεphoroεo-nona-2,3,5-trien-7-yne-l, - diol, 2-diphenylphoεphoroεo-8-phenyl-2,3,5-trien-7-yn-l- ol, 1-(3-diphenylphosphoroso-4-hydroxy-prop-l,2-dienyl)- 2-(3-hydroxy-prop-l-ynyl)benzene and 2-(3- diphenylphosphoroso-3-hydroxy-prop-l,2-dienyl)-3-(3- hydroxy-prop-1-ynyl)naphthalene.

Inventors: MALIGRES PETER E, NICOLAOU KYRIACOS C, MALIGRES, PETER, E., NICOLAOU, KYRIACOS, C.
Applicants: SCRIPPS CLINIC RES, SCRIPPS CLINIC AND RESEARCH FOUNDATION
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P31, A61P35, C07F9