MONOMERIC AND DIMERIC ARYLISOQUINOLINE ALKALOIDS AND DERIVATIVES THEREOF

Abstract: The present invention provides new monomeric derivatives of the C-8'-7 linked naphthylisoquinoline alkaloid dioncophylline D. The invention also provides new C-4 substituted monomeric arylisoquinoline alkaloid derivatives. The present invention furthermore provides novel dimeric arylisoquinoline alkaloids comprised of coupled first and second arylisoquinoline monomers, wherein either or both of said monomer(s) is (are) monomeric compound(s) of the present invention. Monomeric and dimeric compounds of the present invention have medically useful properties, such as antimicrobial properties, more specifically such as antimalarial and antiviral properties. Monomeric compounds of the present invention are also useful as building blocks or intermediates for synthesis of novel dimeric arylisoquinoline alkaloids. Monomeric and dimeric compounds of the present invention may be obtained in substantially pure form by total synthesis, partial synthesis, or derivatization from known synthetic or naturally occurring compounds, and by isolation and purification from plants of the Dioncophyllaceae and Ancistrocladaceae families.

Description: MONOMERIC AND DIMERIC ARYLISOQUINOLINE ALKALOIDS AND DERIVATIVES THEREOF TECHNICAL FIELD OF THE INVENTION The present invention relates to monomeric and dimeric arylisoquinoline alkaloids, derivatives, and compositions thereof. The present invention further relates to methods of preparing and using monomeric and dimeric arylisoquinoline alkaloids and derivatives thereof . BACKGROUND OF THE INVENTION Arylisoqumoline alkaloids exhibiting remarkable antiparasitic and/or antiviral properties have recently been identified. Examples of such arylisoqumolmes can be found in Boyd et al . , U.S. Patent No. 5,455,251; Boyd et al . , U.S. Patent 5,654,432; Franςois et al . , 5,639,761; Francois et al . , U.S. Patent Application Serial No. 08/843,582; Boyd et al . , U.S. Patent 5,409,938; Brmgmann et al . , U.S. Patent 5,571,919; Brmgmann et al . , U.S. Patent Application No. 08/674,359; Brmgmann et al . , U.S. Patent No. 5,552,550; U.S. Patent Application Serial No. 08/674,362; Brmgmann et al . , U.S. Patent No. 5,578,729; Brmgmann et al . , U.S. Patent Application No. 08/721,084; and Brmgmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 127-271. Arylisoqu oline alkaloids of this class include monomeric arylisoqumoline alkaloids ("monomers") and dimeric arylisoqumoline alkaloids ("dimers"). Monomeric arylisoqumoline alkaloids include korupensammes and derivatives thereof, which possess a C-8' to C-5 naphthalene/isoqumolme linkage, and non- korupensammes or other monomeric naphthylisoqumolme alkaloids and derivatives thereof, which lack a C-8' to C- 5 naphthylene/isoqumolme linkage. The monomeric arylisoqu oline alkaloids and derivatives thereof have particular usefulness as preventative and/or therapeutic agents, for example, as antiparasitic agents. For example, the monomeric arylisoqumoline alkaloid dioncophyllme C is among the most potent known antimalarial compounds with m vivo activity against malaria-causmg parasites. Further, the monomeric arylisoqumolmes can be used as precursors for the synthesis of medically useful dimeric arylisoqumoline alkaloids. Dimeric arylisoqumoline alkaloids are exemplified by the miche11amines , which, based on their molecular structure, are comprised of two monomeric arylisoqumoline alkaloid units coupled together (e.g., two monomeric or molecular "halves" ) . Michellammes or related arylisoqumoline alkaloid dimers or derivatives thereof may be either "homodimeπc" (comprised of two monomeric arylisoqumoline halves which are the same) or "heterodimeric" (comprised of two monomeric arylisoqu oline halves which are different) . Dimeric arylisoqumoline alkaloids have highly desirable and eminently useful medical properties that are distinct from the properties of the monomeric naphthylisoqumolme alkaloids which comprise their molecular halves. For example, the michellammes, such as michellamme B, are highly effective inhibitors of the replication and resultant destructive effects of the human immunodeficiency virus (HIV) human cells; moreover, the range of anti-HIV activity of these exemplary dimeric arylisoqumoline alkaloids is exceptionally broad, encompassing diverse strains and isolates of both the manor viral types, HIV-1 and HIV-2 and a wide variety of human host cell lines; and, their mechanism of antiviral activity is distinct from any other known mechanistic class. While the available monomeric and dimeric arylisoqumoline alkaloids have a variety of important medical and chemical uses and applications, new derivatives and structural subtypes of this class of compounds are expected to have additional advantageous properties. For example, new monomeric arylisoqumoline alkaloids can serve as precursors or building blocks for new dimeric arylisoqumoline alkaloids. Furthermore, in any given situation or indication, new monomeric and dimeric arylisoqumoline alkaloids are expected to have useful new or improved medical properties and applications, such as greater therapeutic potency against a particular disease or disease-causing organism, a broader spectrum of therapeutic activity against diverse SUBSTTTUTE SHEET (RULE 26) diseases or disease-causing organisms, enhanced oral bioavailability, less toxicity in a particular host mammal, more advantageous pharmacokmetics and/or tissue distribution in a given host mammal, and the like. In addition, new monomeric and dimeric arylisoqumoline alkaloids are potentially useful for m-vitro assays and antimicrobial research. In view of the foregoing, there exists a need for new medically and chemically useful monomeric and dimeric arylisoqumoline alkaloids and derivatives thereof. The present invention provides such monomeric and dimeric arylisoqumoline alkaloids and derivatives thereof. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein. BRIEF SUMMARY OF THE INVENTION The present invention provides new monomeric derivatives of the C-8'-7 linked naphthylisoqumolme alkaloid dioncophyllme D. The invention also provides new C-4 substituted monomeric arylisoqu oline alkaloid derivatives of dioncophyllme D, ancistrobrevme A, 6-0- demethyl-ancistrobrevme A, yaoundamme A, yaoundamme B, ancistroheynme A, dioncophyllacme A, dioncophyllacme B, dioncophyllme B, dioncopeltme A, dioncophyllme A, dioncophyllme C, dioncolactone A, N-methyl - dioncophyllme A, ancistrobrevme D, ancistrocladme, 5'- 0-demethyl-8-0-methyl-7-epi-dιoncophyllme A, 5'-0- demethyl- 7- epi -dioncophyllme A, dioncophylleme A, hamatme, ancistrobarterme A, 7 - epi -dioncophyllme A, N- formyl -ancistrocladme , N-methyl -ancistrocladme , 6- deoxy-N-methyl -ancistrocladme, N- formyl - O, 0-dimethyl - dioncophyll e C, N- formyl -dioncophyllme C, N- formyl - 8 - O-benzyl -dioncophyllme C, N- formyl-8-O-methyl - dioncophyllme C, N-formyl-8-O-pιvaloyl-dιoncophyllme C, N- formyl -8 -O-acetyl -dioncophyllme C, N- formyl -8 -O- benzoyl -dioncophyllme C, 8 -O-methyl -dioncophyllme C, korupensamme A, korupensamme B, korupensamme C, korupensamme D, and ancistrobrevme B. The present invention furthermore provides novel dimeric arylisoqumoline alkaloids comprised of coupled first and second arylisoqumoline monomers, wherein either or both of said monomer (s) is (are) monomeric compound (s) of the present invention. Monomeric and dimeric compounds of the present invention have medically useful properties, such as antimicrobial properties, more specifically such as antimalarial and antiviral properties. Monomeric compounds of the present invention are also useful as building blocks or intermediates for synthesis of novel dimeric arylisoqumoline alkaloids. Monomeric and dimeric compounds of the present invention may be obtained in substantially pure form by total synthesis, partial synthesis or derivatization from known synthetic or naturally occurring compounds, and by isolation and purification from plants of the Dioncophyllaceae and Ancistrocladaceae families. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A illustrates the structures of dioncophyllme D, ancistrobrevme A, 6-O-demethyl- ancistrobrevme A, and yaoundamme A. Figure IB illustrates the structure of yaoundamme B, ancistroheynme A, dioncophyllacme A, and dioncophyllacme B. Figure 2A illustrates the structures of dioncophyllme B, dioncopeltme A, dioncophyllme A, and dioncophyllme C. Figure 2B illustrates the structure of dioncolactone A, N-methyl -dioncophyllme A, ancistrobrevme D, and ancistrocladme. Figure 2C illustrates the structures of 5'-0-demethyl-8-0-methyl-7- epi -dioncophyllme A, 5'-0-demethyl-7-ep -dioncophyllme A, dioncophylle e A, and hamatme. Figure 2D illustrates the structure of ancistrobarterme A, 7-ep - SUBSTΪTUTE SHEET (RULE 26) dioncophyllme A, N- formyl -ancistrocladine, and N-methyl - ancistrocladine . Figure 2E illustrates the structure of 6 -deoxy-N-methyl -ancistrocladine , N- formyl -0, O-dimethyl- dioncophylline C, N- formyl -dioncophylline C, and N- formyl -8 -O-benzyl-dioncophylline C. Figure 2F illustrates the structure of N- formyl-8-0-methyl- dioncophylline C, N- formyl -8 -O-pivaloyl-dioncophylline C N- formyl -8-0-acetyl-dioncophylline C, and N- formyl -8-0- benzoyl -dioncophyllme C. Figure 2G illustrates the structure of 8 -0-methyl-dioncophylline C, korupensamine A, korupensamine B, korupensamine C, korupensamine D, and ancistrobrevine B. Figure 3 illustrates key spectroanalytical data and analyses used to establish the structure of 8-0- methyldioncophylline D: (a) selected 1 H ΝMR chemical shifts (δ values in ppm) , (b) HMBC correlations, and (c) ΝOE interactions. Figure 4 illustrates the degradation procedure and the key ΝOE interactions used to demonstrate the relative and absolute configuration at the stereogenic centers of the tetrahydroisoquinoline portion of 8-0-methyl- dioncophyl1ine D . Figures 5A-5B illustrate key spectroanalytical data and analyses used to establish the structure of dioncophyllinol D. Figure 5A: selected 1 H ΝMR chemical shifts (δ values in ppm) and ΝOE interactions. Figure 5B: HMBC correlations. Figure 6 illustrates the degradation procedure and key ΝOE interactions used to demonstrate the relative and absolute configuration at the stereogenic centers of the tetrahydroisoquinoline portion of dioncophyllinol D. Figure 7 illustrates the P- and M-atropisomeric forms of dioncophyllinol, rapidly interconverting at room temperature . Figure 8 illustrates various methods of preparation of 8 -O-methyl -dioncophyllme D. Figure 9 illustrates a method of preparing dioncophylline D and 8 -O-methyldioncophylline D by total synthesis via intermolecular biaryl coupling. Figure 10 illustrates preparation of dioncophylline D and 8 -O-methyl -dioncophyllme D by total synthesis via intramolecular biaryl coupling. Figure 11 illustrates a method of preparing dioncophyllinol D from dioncophyllinone D. Figure 12 illustrates a method of preparing of 4- hydroxyisoquinoline building blocks with 1R, 3R- configuration. Figure 13 illustrates preparation of 4- hydroxyisoquinoline building blocks with 1S,3S- configuration . Figure 14 illustrates a method of forming the naphthalene/isoquinoline biaryl axis by an intermolecular transition metal catalyzed coupling. Figure 15 illustrates a method of preparing a C-4 oxo arylisoquinoline from dioncophyllinol D by partial synthesis or total synthesis. Figure 16 illustrates a method of preparing a C-4 oxo arylisoquinoline by total synthesis. Figure 17 illustrates a method of preparing a homodimeric arylisoquinoline alkaloid. Figure 18 illustrates a method of preparing a homodimeric arylisoquinoline alkaloid. Figure 19 illustrates a method of preparing a protected and activated monomeric phenylisoquinoline "half" . Figure 20 illustrates a method of preparing a heterodimeric arylisoquinoline alkaloid comprising two different monomeric arylisoquinoline "halves" . DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides derivatives of dioncophylline D, wherein the configuration at C-1 or C-3 is instead S; one or more phenolic hydroxyl group (s) is instead an ester, sulfonate ester, or ether group; a methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is instead an aromatic hydrogen substituent; the secondary amme site is instead an amide, sulfonamide, tertiary amme, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is instead halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 is instead H; and/or the tetrahydroisoquinoline is instead a dihydroisoqumolme; with the proviso that said derivative is not ancistrobrevme A, 6-O-demethyl-ancιstrobrevme A, yaoundamme A, yaoundamme B, or ancistroheynine A. Heretofore the only reported monomeric arylisoqumoline alkaloid compounds known to contain a C- 8' to C-7 naphthalene/isoquinoline linkage were dioncophyllme D, ancistrobrevme A, 6-O-demethyl- ancistrobrevme A, yaoundamme A, yaoundamme B, and ancistroheynine A (Figures 1A-1B) . These compounds were originally isolated and purified from plants of the Dioncophyllaceae and Ancistrocladaceae families (Brmgmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, p. 151, pp. 163-164); Hallock et al . , Tetrahedron, 53 , 8121-8128 (1997); Brmgmann et al . , Phytochem . , 43 , 1405-1410 (1996)) . Furthermore, the only reported monomeric naphthylisoqumolme alkaloids known to contain any substituent other than a hydrogen at the C-4 position of the isoquinoline ring are the dioncophyllacmes A and B (Figure IB) , wherein the isoquinoline ring is fully aromatic (Brmgmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 152-154) . There has been no literature report of any dimeric arylisoqumoline alkaloid wherein either or both molecular half (halves) comprise a compound of the present invention. The present invention provides useful new monomeric and dimeric arylisoqumoline alkaloid derivatives containing the C-8' to C-7 naphthalene/isoquinoline linkage. It is another object of the present invention to provide useful new monomeric and dimeric arylisoqumoline alkaloid derivatives containing substituent (s) other than hydrogen at the C-4 posιtιon(s) of the isoquinoline rmg(s). Specifically excluded from the compounds of the present invention are the previously disclosed monomeric compounds: dioncophyllme D, ancistrobrevme A, 6-O-demethyl-ancιstrobrevme A, yaoundamme A, yaoundamme B, ancistroheynine A, dioncophyllacme A, and dioncophyllacme B (Figures 1A- 1B) . Also specifically excluded from the present invention are other known (Brmgmann and Porkorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 127-271) monomeric arylisoqumoline alkaloid compounds illustrated in Figures 2A-2G. Compounds of the present invention comprise new monomeric and dimeric derivatives of dioncophyllme D as well as new monomeric and dimeric derivatives of the other compounds shown in Figures 1-2. The monomeric compounds of the present invention are useful as synthetic intermediates or building blocks for making useful new dimeric arylisoqumoline alkaloid compounds. Furthermore, the monomeric as well as the dimeric compounds of the present invention have medically useful and other useful properties, particularly including antimalaπal and antiviral properties. Structures To make it easier to compare arylisoqumoline alkaloids of the present invention of different coupling types, contrary to IUPAC numbering conventions, and consistent with previous work by the inventors (Brmgmann SUBSTTTUTE SHEET (RULE 26) and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.) Academic Press, New York, 1995, pp. 127-271), the naphthalene portion of the alkaloids is hereinafter numbered in the same way. In other words, there is always attributed a 2-methyl-4 , 5-dιoxy-substιtutιon pattern to the naphthalene, independent from the site of the axis. Definitions For clarification of the chemical structures described herein, the following definitions apply. By arylisoqumoline homodimer is meant a dimeric alkaloid containing two monomeric arylisoqumoline halves, wherein each half is the same. By arylisoqumoline heterodimer is meant a dimeric alkaloid containing two monomeric arylisoqu oline halves, wherein each half is different. By C.-C 6 alkyl is meant straight or branched-chain C- L -Cg alkyl groups. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary-butyl, n-pentyl, isopentyl, and n-hexyl . By aryl is meant an organic radical derived from an aromatic hydrocarbon. Examples of aryl groups include but are not limited to phenyl, o- , m- , and p- hydroxyphenyl , and naphthyl . By aliphatic is meant an organic radical derived from an open straight or branched hydrocarbon chain. Examples of aliphatic radicals include alkanes, alkenes, and alkynes. Specific examples of aliphatic radicals which can be used m the present invention include, but are not limited to, C.-C 6 alkyl radicals, straight or branched. Medical and Other Uses The new dimeric arylisoqumoline alkaloids and derivatives thereof are expected to have at least those medicinal properties possessed by previously disclosed monomeric and dimeric naphthylisoquinoline alkaloids (see, e.g., Boyd et al . , U.S. Patent No. 5,455,251; Franςois et al . , U.S. Patent No. 5,639,761). However, depending upon the particular disease and host to be treated, a compound of the present invention will be distinctly advantageous in a given situation. Medically useful properties of the compounds of the present invention can be readily confirmed by one knowledgeable and skilled in the art by use of any of a variety of methods which have been published or otherwise disclosed elsewhere. For example, antiviral properties, particularly anti-HIV properties, can be confirmed as described in Boyd et al . , U.S. Patent No. 5,455,251. Also, for example, in vi tro and in vivo antimalarial activity may be confirmed as described in Franςois et al . , U.S. Patent No. 5,639,761 and Boyd et al . , U.S. Patent No. 5,409, 938. The compounds of the present invention also are useful in a variety of in vi tro applications. Such in vi tro applications include biochemical assays, as well as chemical syntheses and viral research. The compounds of the present invention are also useful as synthetic intermediates for the preparation of monomeric and dimeric arylisoquinoline alkaloids. Preparation, Isolation, and Purification One skilled in the art will readily appreciate that, based upon prior disclosures, and in conjunction with other now well-established methods and procedures, compounds of the present invention can be obtained, purified, and provided in substantially pure form from natural sources, particularly from plants of the Dioncophyllaceae and Ancistrocladaceae families, and/or can be prepared by chemical modificatio (s) or derivatization (s) of naturally occurring arylisoquinoline alkaloids (Boyd et al . , U.S. patent No. 5,455,251; Boyd et al . , U.S. Patent No. 5,654,432; Franςois et al , U.S. Patent No. 5,639,761; Boyd et al , U.S. Patent No. 5,409,938; Bringmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 127-271) . Chemical structures of isolated and purified compounds of the present invention can be elucidated and/or verified by a variety of procedures, particularly spectroanalytical procedures, well-known to experienced practitioners of the art. Example 1 describes the isolation and purification, from a plant, of exemplary compounds of the present invention: dioncophyllinol D and 8-O-methyldioncophylline D. Example 2 describes the detailed structure proof of an exemplary compound of the present invention: dioncophyllinol D. In addition to isolation, purification and derivatization of compounds from natural sources, compounds of the present invention can be obtained by partial and/or total synthesis. For instance, one skilled in the art will readily appreciate that, based upon prior disclosures (Bringmann et al . , U.S. Patent No. 5,571,919; Bringmann et al . , U.S. Patent No. 5,552,550; Bringmann et al , U.S. Patent Application No. 08/721,084; Bringmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.) , Academic Press, New York, 1995, pp. 127- 271), monomeric and dimeric compounds of the present invention can be chemically synthesized using naturally occurring and/or fully synthetic precursors, intermediates or building blocks. Example 3 illustrates partial and total synthesis strategies for preparing exemplary monomeric compounds of the present invention using approaches defined in previous disclosures and in conjunction with other now well-established reactions and procedures (Bringmann et al . , U.S. Patent No. 5,552,550; Bringmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 127- 271) . Example 4 illustrates partial and total synthesis strategies for preparing exemplary dimeric compounds of the present invention using approaches defined in previous disclosures and in conjunction with other well- established reactions and procedures (Brmgmann et al . , U.S. Patent No. 5,571,919; Bringmann et al . , U.S. Patent No. 5,578,729; Br gmann et al . , U.S. Patent Application No. 08/721,084; Brmgmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, pp. 127-271) . The Present Inventive Compounds Accordingly, the present invention provides useful new monomeric derivative compounds of dioncophyllme D, wherein at least one or more of the following modifications is incorporated: the configuration at C-1 or C-3 is instead S; one or more phenolic hydroxyl group (s) is (are) instead ester, sulfonate ester, or ether group (s) ; the methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is (are) instead (an) aromatic hydrogen substituent (s) ; the secondary amme site is instead an amide, sulfonamide, tertiary amme, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is (are) instead halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 is instead H; a tetrahydroisoquinoline is instead a dihydroisoqumolme . The present invention further provides useful new monomeric derivative compounds of dioncophyllme D, ancistrobrevme A, 6-O-demethyl-ancιstrobrevme A, yaoundamme A, yaoundamme B, ancistroheynine A, dioncophyllme B, dioncopeltme A, dioncophyllme A, dioncophyllme C, dioncolactone A, N-methyl - dioncophyllme A, ancistrobrevme D, ancistroclad e, 5'- 0-demethyl-8-0-methyl-7-epι-dιoncophyllme A, 5'-0- demethyl -7 - epi -dioncophylline A, hamatme, ancistrobarterme A, 7 - epi -dioncophylline A, N- formyl - SUBSTTTUTE SHEET (RULE 26) ancistrocladine, N-methyl -ancistrocladine , 6 -deoxy-N- methyl -ancistrocladine, N- formyl - O, O-dimethyl- dioncophylline C, N- formyl -dioncophylline C, N- formyl -8- O-benzyl-dioncophylline C, N- formyl -8-0-methyl - dioncophylline C, N-formyl-8-0-pivaloyl-dioncophylline C, N- formyl- 8 -O-acetyl-dioncophylline C, N- formyl -8-0- benzoyl-dioncophylline C, and 8 -O-methyl -dioncophyllme C, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, or may be configuratively unstable; one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl , halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 may instead be H; a tetrahydroisoquinoline may instead be a dihydroisoquinoline; and (b) a substituent at C-4 is C--C 6 alkyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano or oxo. The present invention further provides new monomeric derivative compounds of dioncophylline D, ancistrobrevine A, 6-0-demethyl-ancistrobrevine A, yaoundamine A, yaoundamine B, ancistroheynine A, dioncophyllacme A, dioncophyllacme B, dioncophylline B, dioncopeltine A, dioncophylline A, dioncophyllme C, dioncolactone A, N- methyl -dioncophylline A, ancistrobrevine D, ancistrocladine , 5' - O-demethyl - 8 -O-methyl - 7 - epi - dioncophylline A, 5'-0-demethyl-7-epi-dioncophylline A, dioncophylleine A, hamatine, ancistrobarterine A, 7-epi- dioncophylline A, N- formyl ancistrocladine, N-methyl - ancistrocladine , 6 -deoxy-N-methyl - ancistrocladine , N- formyl-O, O-dimethyl-dioncophylline C, N- formyl - dioncophylline C, N- formyl- 8 -O-benzyl -dioncophyllme C, N- formyl-8-0-methyl-dioncophylline C, N-formyl-8-0- pivaloyl -dioncophylline C, N- formyl-8-O-acetyl- dioncophylline C, N- formyl -8 -O-benzoyl -dioncophylline C, and 8 -O-methyl -dioncophylline C, wherein: (a) the configurations at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, or may be configuratively unstable; one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be C λ -C 6 alkyl, acyl , halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (b) the isoquinoline is a fully aromatic isoquinoline; and (c) a substituent at C-4 is acyloxy, alkoxy, aryloxy, glycosyloxy or oxo. The present invention further provides useful new monomeric derivative compounds of korupensamine A, korupensamine B, korupensamine C, korupensamine D, and ancistrobrevine B, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, or may be configuratively unstable; one or more phenolic hydroxyl grou (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and (b) a substituent at C-4 is C.-C 6 alkyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano or oxo. The present invention further provides useful new monomeric derivative compounds of korupensamine A, korupensamine B, korupensamine C, korupensamine D, and ancistrobrevine B wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/ isoquinoline axis may be P or M, or may be configuratively unstable; one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl , halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 may instead be H; the tetrahydroisoquinoline may instead be a dihydroisoquinoline or a fully aromatic isoquinoline; (b) a substituent at C-4 is acyloxy, alkoxy, aryloxy, glycosyloxy or oxo; and (c) at least one aromatic hydrogen substituent is instead an acyl or alkyl, and/or a substituent at C-2' cannot be methyl when substituents at C-1 and C-3 are both methyl. The present invention further provides useful new dimeric arylisoquinoline alkaloids comprised of coupled first and second arylisoquinoline monomers, wherein either or both of said monomer (s) is (are) monomeric compound (s) of the present invention. The present invention further provides 4-substituted monomeric arylisoqumolmes of the formula: OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-terminal substituent on the isoquinoline ring, preferably H, C.-C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C.-C 3 alkyl, more preferably — ■■ H, " H, CH 3 , or CH 3 ; R , R D , and R° may be the same or different and each may be H, C x - C β alkyl, arylmethyl , or aryl, preferably H or C.-C 6 alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably C.-C 6 alkyl, acyl, halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoqumolme ring or a fully saturated isoquinoline ring; and R 7 can be any functional group, preferably selected from the group consisting of H, C- L -C J alkyl, acyl, halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, and cyano. The present invention further provides 4 -substituted dimeric arylisoqumolmes of the formula: OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably C.-C 6 alkyl, acyl, aryl, halo, nitro, ammo, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-termmal substituent on the isoquinoline ring, preferably H, C_-C c alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C.-C 3 alkyl, more preferably "~" ■ H, ' H, CH, or CH 3 ; R , R , and R may be the same or different and each may be H, C.-C 6 alkyl, arylmethyl, or aryl, preferably H or alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and R 7 is arylisoquinoline of the formula: ARYLISOQUINOLINE I OR ARYLISOQUINOLINE II OR ARYLISOQUINOLINE III wherein either A or B can be any suitable substituent or precursor thereof, preferably C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B are both H or together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-terminal substituent on the isoquinoline ring, preferably H, C.-C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C.-C 3 alkyl, more preferably -— H, H, — CH 3 , or CH 3 ; R 5 , R 6 , and R 8 may be the same or different and each may be H, C.-Cg alkyl, arylmethyl , or aryl, preferably H or C.-C 6 alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably alkyl, acyl, halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and the tetrahydroisoquinoline ring may instead be a dihydroisoqumolme ring or a fully saturated isoquinoline ring. The present invention further provides 4-substituted dimeric arylisoquinolines of the formula: OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably -Cg alkyl, acyl, aryl, halo, nitro, ammo, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-termmal substituent on the isoquinoline ring, preferably H, C,-C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C : -C 3 alkyl, more preferably ""^ H, " H, —- ■ CH 3 , or CH 3 ; R 5 , R 6 , and R θ may be the same or different and each may be H, C.-C 3 alkyl, arylmethyl , or aryl, preferably H or C,-C 6 alkyl; one or more aromatic hydrogen substituen (s) may instead be any functional group or organic radical, preferably C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and R 7 is a radical having a structure selected from the group consisting of derivatives of dioncophylline D, wherein the configuration at C-1 or C-3 is instead S; one or more phenolic hydroxyl group (s) is instead an ester, sulfonate ester, or ether group; a methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is instead an aromatic hydrogen substituent; the secondary amine site is instead an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is instead halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 is instead H; and/or the tetrahydroisoquinoline is instead a dihydroisoquinoline; with the proviso that said derivative is not ancistrobrevine A, 6-0-demethyl- ancistrobrevine A, yaoundamine A, yaoundamine B, or ancistroheynine A. The present invention further provides 4 -substituted dimeric arylisoqumolmes of the formula: SERIES I OR OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-terminal substituent on the isoquinoline ring, preferably H, C.-C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C x -C 3 alkyl, more preferably ~~~™ H, ' H, CH, or CH,; R 5 R 6 and R 8 may be the same or different and each may be H, C.-C 6 alkyl, arylmethyl, or aryl, preferably H or C.-C 6 alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and R 7 is a radical selected from the group consisting of derivatives of dioncophylline D, ancistrobrevine A, 6-O-demethyl- ancistrobrevine A, yaoundamine A, yaoundamine B, ancistroheynine A, dioncophylline B, dioncopeltine A, dioncophylline A, dioncophylline C, dioncolactone A, N- methyl-dioncophylline A, ancistrobrevine D, ancistrocladine, 5'-0-demethyl -8 -O-methyl -7- epi - dioncophylline A, 5'-0-demethyl-7-epi-dioncophylline A, hamatine, ancistrobarterine A, 7 - epi -dioncophylline A, N- formyl ancistrocladine, N-methyl - ancistrocladine , 6- deoxy-N-methyl -ancistrocladine, N- formyl -0, O-dimethyl- dioncophylline C, N- formyl -dioncophylline C, N- formyl - 8 - O-benzyl -dioncophylline C, N- formyl -8 -O-methyl - dioncophylline C, N-formyl - 8 - O-pivaloyl -dioncophylline C, N- formyl -8-0-acetyl-dioncophylline C, N- formyl -8 -0- benzoyl-dioncophylline C, and 8 -O-methyl -dioncophylline C, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 may instead be H; the tetrahydroisoquinoline may instead be a dihydroisoquinoline; and (b) a substituent at C-4 is C.-C β alkyl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano or oxo. The present invention further provides 4 -substituted dimeric arylisoqumolmes of the formula: SERIES I OR SERIES I I OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N- terminal substituent on the isoquinoline ring, preferably H, C 1 -C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C^C j alkyl, more preferably - mmm H, H, ——' CH 3 , or CH 3 ; R 5 , R 6 , and R 8 may be the same or different and each may be H, C 1 -C 6 alkyl, arylmethyl , or aryl, preferably H or C.-C 6 alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and R 7 is a radical having a structure selected from the group consisting of derivatives of dioncophylline D, ancistrobrevine A, 6-0- SUBST1TUTE SHEET (RULE 26) demethyl -ancistrobrevine A, yaoundamine A, yaoundamine B, ancistroheynine A, dioncophyllacine A, dioncophyllacme B, dioncophylline B, dioncopeltine A, dioncophylline A, dioncophylline C, dioncolactone A, N-methyl - dioncophylline A, ancistrobrevine D, ancistrocladine, 5'- 0-demethyl-8-0-methyl-7-epi-dioncophylline A, 5'-0- demethyl -7 -epi-dioncophylline A, dioncophylleine A, hamatine, ancistrobarterine A, 7 - epi-dioncophylline A, N- formyl ancistrocladine, N-methyl -ancistrocladine, 6- deoxy- N-methyl -ancistrocladine, N- formyl - O, O-dimethyl- dioncophylline C, N- formyl -dioncophylline C, N- formyl - 8 - 0-benzyl -dioncophylline C, N- formyl -8 -O-methyl - dioncophylline C, N-formyl -8 -O-pivaloyl -dioncophylline C, N- formyl- 8 -O-acetyl-dioncophylline C, N- formyl -8-0- benzoyl -dioncophylline C, and 8 -O-methyl -dioncophylline C, wherein: (a) the configurations at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (b) the isoquinoline is instead a fully aromatic isoquinoline; and (c) a substituent at C-4 is acyloxy, alkoxy, aryloxy, glycosyloxy or oxo; with the proviso that said compound is not dioncophyllacine A or dioncophyllacine B. The present invention further provides 4 -substituted dimeric arylisoqumolmes of the formula: SERIES II OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-terminal substituent on the isoquinoline ring, preferably H, C : -C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C 1 -C 3 alkyl, more preferably ~"" ■ H, H, CH, or CH,; R b R b and R 8 may be the same or different and each may be H, C.-C 6 alkyl, arylmethyl , or aryl, preferably H or C.-C 6 alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably -Cg alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and R ' is a radical having a structure selected from the group consisting of derivatives of korupensamine A, korupensamine B, korupensamme C, korupensamine D, and ancistrobrevme B, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amme sιte(s) may instead be an amide, sulfonamide, tertiary amme, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amme sιte(s) may instead be a secondary amme; one or more aromatic hydrogen substituent (s) may instead be halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and (b) a substituent at C-4 is C.-C 6 alkyl, halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano or oxo. The present invention further provides 4-substιtuted dimeric arylisoqumolmes of the formula: SERIES I OR SERIES II OR SERIES III wherein either A or B can be any suitable substituent or precursor thereof, preferably C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together form a keto group (=0) , a thio group (=S) , or a ketal of the formula -0(CH 2 ) n 0-, wherein n is an integer from 2-4; R 2 can be any suitable N-terminal substituent on the isoquinoline ring, preferably H, C.-C 6 alkyl, an amide, or sulfonamide; R 1 and R 3 may be the same or different, preferably H or C.-C 3 alkyl, more preferably —™ H, H, • —— CH 3 , or CH 3 ; R 5 , R 6 , and R 8 may be the same or different and each may be H, C.-C 6 alkyl, arylmethyl , or aryl, preferably H or C.-C 6 alkyl; one or more aromatic hydrogen substituent (s) may instead be any functional group or organic radical, preferably alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and R 7 is a radical having a structure selected from the group consisting of derivatives of korupensamine A, korupensamine B, korupensamine C, korupensamine D, and ancistrobrevine B, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group may instead be an aromatic hydrogen substituent; one or more secondary amine site may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site may instead be a secondary amine; one or more aromatic hydrogen substituent may instead be C.-C e alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH, may instead be H; the tetrahydroisoquinoline may instead be a dihydroisoquinoline or a fully aromatic isoquinoline; (b) a substituent at C-4 is acyloxy, alkoxy, aryloxy, glycosyloxy or oxo; and (c) at least one aromatic hydrogen substituent is instead an acyl or C j -Cg alkyl, and/or a substituent at C-2' is not methyl when C-1 and C- 3 are each substituted with a methyl. Compositions The present invention further provides compositions comprising one or more of the present inventive compounds and a carrier therefor. With respect to medical uses, the present inventive composition will be a parmaceutical composition, the present inventive compound will be present in a therapeutic or prophylatic amount, and the carrier will be a pharmaceutically acceptable carrier. Examples The following examples further illustrate the present invention but, of course, should not be construed as in any way limiting its scope. In the following examples, IR spectra were recorded on a Perkin-Elmer 1420 infrared spectrophotometer . Mass spectra were measured at 70 eV on a Finnigan MAT 8200 or on a Varian MAT CH7 mass spectrometer. : H and 13 C NMR spectra were recorded on a Bruker DMX 600 spectrometer using CD 3 OD (δ 3.33 ppm) as the internal reference. HPLC purifications were carried out with a Waters 600E pump, a Nova-Pak C 18 (Waters, 200x25 mm, 6μm, integrated guard pak) column, and a Waters 996 photodiode array detector. Triphyophyllum pel tat m plants were collected and identified by L. Ake Assi in November, 1991, and by L. Ake Assi and G. Bringmann in March, 1996 in the Pare de Taϊ, West Ivory Coast. Herbarium specimens of these collections were placed on deposit at the Centre National de Floristique, Abidjan, Ivory Coast, and at the Institut fύr Organische Chemie, Wύrzburg, Germany. EXAMPLE 1 This example illustrates the procedure for isolation and purification of dioncophyllinol D. Dried leaves of T. peltatum (40 g) were powdered and macerated for 2 days with 400 mL MeOH/1 N HCl (1:1 v/v) at room temperature with ultrasonic assistance. After removal of the MeOH, the aqueous residue was re-extracted with 1.5 L of chloroform to yield 180 mg of a brownish crude extract, which was chromatographed over silica gel (60 g, deactivated with 7.5% NH 3 ) using CH 2 Cl 2 /MeOH (95:5) as the eluent to yield a fraction of 22 mg containing the new compound. Further purification was done by semipreparative HPLC using a Nova-Pak C 18 (200x25 mm, 6 μm) column with MeOH/H 2 0 (6:2) as the eluent to give 6 mg (0.015%) of a yellow solid, mp 209°C; α D 25 + 17° (c=0.046, CHC1 3 ) , IR (KBr) 3395, 3195, 3000, 1660, 1410, 1190, 1110 cm 1 ; H NMR (CD 3 OD, 600 MHZ) δ 7.32 (IH, d, J " =8.6 Hz, 6'- H) , 7.27 (IH, d, J=8.6 Hz, 7'-H) , 7.25 (IH, d J=8.1 Hz, 6- H) , 7.24 (IH, s, l'-H) , 7.00 (IH, d, J=8.1 Hz, 5-H) , 6.85 (IH, d, J " =0.9, Hz, 3'-H) , 4.66 (IH, q, J=6.8 Hz, 1-H), 4.50 (IH, d, J " =2.2 Hz), 4.08 (3H, s, 4'-OCH 3 ) , 3.66 (IH, dq, J " =2.2 Hz, 6.7 Hz, 3-H), 2.47 (3H, s, 2'-CH 3 ) , 1.60 (3H, d, J=6.8 Hz, I-CH 3 ) , 1.42 (3H, d, J=6.7 Hz, 3-CH 3 ) ; 13 C NMR (CD 3 OD, 150 MHZ) δ 15.09 (3-CH 3 ) , 17.21 (1-CH 3 ) 21.89 (2'-CH 3 ) , 49.79 (3-C) , 50.17 (1-C) , 56.93 (4'-OCH 3 ) , 67.07 (4-C) , 108.40 (3'-C) , 114.31 (4a'-C) , 118.91 (8a'-C) , 120.45 (6'-C) , 121.69 (l'-C) , 122.23 (8a-C) , 122.78 (5-C) , 128.58 (7-C) , 131.20 (7'-C) , 132.60 (6-C) , 135.66 (5a'-C) , 138.15, 138.22 (8'-C, 2'-C) , 151.60 (8-C) , 151.72 (5'-C) , 157.51 (4'-C) ; MS m/z (rel. int.) 379 (M + , 10.7) , 364 (M- CH 3 , 100) , 348 (M-OCH 3 , 11) ; HRMS m/z 379.177 (MJ C 23 H 25 0 4 N, requires 379.178) . These and other spectroanalytical data and analyses were used to elucidate the identity of this isolated and purified compound as dioncophyllinol D (Figure 7) . EXAMPLE 2 This example illustrates the procedure for isolation, purification, and structure elucidation of 8- O-methyldioncophyllme D. Dried leaves of T. pel tatum (19.4g) were powdered and macerated two times for 2 days with 200 mL MeOH/l N HCl (1:1 v/v) at ambient temperature with ultrasonic assistance. After evaporation of the MeOH in vacuo, the aqueous residue was re-extracted two times with 1 L portions of chloroform to yield 317 mg of a yellow crude extract, which was chromatographed over silica gel (40 g, deactivated with 7.5% NHJ using CH 2 Cl 2 /MeOH (95:5) as the eluent to yield a fraction of 18 mg containing 8-O-methyldioncophyllme D. Further purification was done first by semipreparative TLC (CH 2 Cl 2 /MeOH (95:5), R f =0.63) and then by semipreparative HPLC using a Nova-Pak C 18 (200x25 mm, 6 μm) column with MeOH/H 2 0 (6:2) as the eluent to give 4 mg (0.021%) as a yellow solid, mp 228-232°C; α D 2S + 21° (c=0.051, CHC1 3 ) , IR (KBr) : v=3400, 3920, 1650, 1400, 1250, 1090 cm 1 . : H-NMR (200.1 MHZ CDC1J : δ=1.22 (3H, d, J=6.1 Hz, 3-CH 3 ), 1.53 (3H, d, J=6.4 Hz, 1-CH j ) , 2.40 (3H, s, 2'-CH 3 ), 2.69 (IH, dd, J=15 . 56 , 2.74 Hz, 4-H) , 2.91 (IH, m, 3-H), 3.36, (3H, s, 8-OCH 3 ) , 3.95 (3H, s, 5'-OCH 3 ) , 4.36 (IH, q, .7=5.8 Hz, 1-H) , 6.57 (IH, d, J=1 . 2 Hz, 3'-H) , 6.83 (IH, d, J=8.1 Hz, 5-H) , 7.21 (IH, d, J=8.1 Hz, 6-H) , 7.22 (IH, d, ,7=1.2 Hz, l'-H) , 7.25 (IH, d, -7=8.45 Hz, 7'-H) , 7.36 (IH, d, J=8.45 Hz, 6'-H) , 13 C-NMR (63.25 MHZ, CDCl 3) δ=20.30 (3- CH 3 ) , 21.90 (1-CH j and 2'-CH 3 ) , 37.00 (4-C),49.53 (3-C), 50.93 (1-C) , 56.09 (4'-OCH 3 ) , 60.11 ( 8 -OCHJ , 106.55 (3'- C) , 113.31 (4a'-C) , 118.00 (6-C), 120.84 (l'-C), 123.72 (5-C) , 127.20 (8a-C) , 129.72 (7-C) , 130.31 (7'-C), 130.93 (6'-C) , 136.29 (8a'-C), 135.85 (2'-C) , 136.45 (4a-C) , 150.89 (5'-C) , 155.95 (8-C), 156.18 (4'-C), MS (70 εV) : m/z (%) = 378 (3.81 [M+] , 377 (13.43) [M+-H] , 362 (100) [M+- CH 3 ] HRMS: m/z 362.175 (M+-CH 3 , CH 23 H 24 0 3 N, 362.176). These and other spectroanalytical data and analyses were used to elucidate the identity of this isolated and purified compound as 8-O-methyldιoncophyllme D. Figure 3 illustrates the key spectroanalytical data and analyses (H NMR chemical shifts, NOE interactions and HMBC correlations) used to demonstrate the structure. Figure 4 illustrates the key NOE interactions and degradation procedures to demonstrate the stereochemistry. Example 3, which follows, illustrates in greater detail the use of these types of data, analyses, and procedures for demonstration of structures and stereochemistry of compounds of the present invention, specifically m this instance for the exemplary compound, dioncophyllinol D. EXAMPLE 3 This example illustrates the structure elucidation of dioncophyllinol D. The X H NMR spectrum of dioncophyllinol D (see Example 1) showed the typical signals for a naphthylisoqumolme alkaloid. Different, for example, from dioncophyll e A (Bringmann et al . Tetrahedron Lett . , 31 , 643-646 (1990)), the coupling pattern of the aromatic protons, m particular the presence of four aromatic doublets and two singlets, suggested the biaryl axis to be positioned in the 6' or in the 8' position of the naphthalene part. The mam difference compared to the X H NMR spectrum of dioncophyllme A, however, was the lack of the typical diastereotopic protons at C-4 with expected chemical shifts of 2.7 (dd) and 3.4 (dd) ppm. Instead, a distinctly low-field shifted doublet (J=2.2 Hz) was observed at 4.5 ppm (Figure 5A) , hinting at the presence of a CH-X array at C-4, which was furthermore confirmed by the multiplicity of H-3 (δ 3.7 ppm, dq, J=2.2 Hz, 6.9 Hz) . From the chemical shift of H-4 (δ 4.5 ppm) , an OH group could be assumed to be located at C-4. The presence of a novel 4-hydroxylated naphthyltetrahydroisoquinoline alkaloid was corroborated by HRMS, which delivered the molecular formula C 23 H 25 N0 4 (M+, m/z = 379.177) . NOE interactions (Figure 5A) of H-5 with both H-4 and H-6 suggested the biaryl axis was located at C-7 of the isoquinoline part. This was confirmed by an HMBC interaction (Figure 5B) between H-6 and C-8', across the biaryl axis. The position of the biaryl linkage in the naphthalene part at C-8' was demonstrated by HMBC correlations (Figure 5B) between H-l' and C-8' as well as the aforementioned interaction between H-6 and C-8', which likewise ruled out a coupling via C-6'. In agreement with this 7, 8'-coupling, CH 3 -2' exhibited NOE effects (Figure 5A) both with H-l' and H-3', thus excluding a positioning of the axis in that methyl-substituted ring of the naphthalene part, which was further indicated by the normal, non-high-field shifted absorption of CH 3 -2' (δ 2.5 ppm) . The methoxy group in the naphthalene part was located at C-4' (and not C-5') as evidenced by an NOE effect with H-3' (Figure 5A) and an HMBC interaction with C-4' (Figure 5B) . This novel alkaloid with the very rare 7,8' ( D- type') coupling pattern and the unprecedented extra OH- group at C-4, subsequently named dioncophyllinol D, is the first naphthylisoquinoline alkaloid with three stereocenters at C-1, C-3, and C-4. From an NOE interaction between H-3 and CH 3 -1 (Figure 6) , which were thus both axial and cis to each other, a relative trans- configuration of the two methyl groups at C-1 and C-3 was deduced. The small coupling constant (J = 2.2 Hz) between the axial proton at C-3 and H-4 indicated the latter to be equatorial, revealing a relative cis- configuration of OH-4 and CH 3 -3. This was confirmed by another clear NOE interaction between H-3 and H-4, which excluded a trans-diaxial position of these two protons and thus an equatorial position of the oxygen substituent at C-4. For the given cis-configuration at C-3 and C-4, both trans relative to CH 3 -1, a semiempirical conformational analysis [AMI (Dewar et al . , J. Am. Chem . Soc , 107, 3902-3909 (1995)) as implemented in VAMP 5.0 (Rauhut et al . , VAMP 5.0, Oxford Molecular Limited, Oxford Science Park, Standford on Thames, Oxford)] indicated the preferred presence of a half-chair conformation as seen in Figure 6, in full agreement with the NOE data and coupling constants observed. For the determination of the absolute configuration, the oxidative degradation procedure as disclosed in Bringmann et al . , Phytochemistry, 43 , 1393-1409 (1996), was used. Unlike all the other naphthyltetrahydroisoquinoline alkaloids degraded so far, no 3 -amino butyric acid was to be expected because of the additional hydroxy function at C-4. In the present case, D-alanine was liberated. Unambiguous results were obtained from the D-alanine analyzed, whose absolute configuration clearly showed C-1 to be P-configured. From this and the relative configuration as elucidated above, the stereocenters C-3 and C-4 were also deduced to have the P-configuration as illustrated in Figure 6. The last remaining stereochemical information required was the chirality at the biaryl axis, i.e., the question whether dioncophyllinol D was correctly represented by the P or M form (Figure 7) . A calculation of the CD behavior expected for these two imaginable atropo-diastereomeric forms of dioncophyllinol D using the CNDO/S-C1 method (Bringmann et al . , Tetrahedron, 53 , 2817-2822 (1997)) and comparison of the theoretically predicted CD spectrum with the experimental one of the natural product gave no significant agreement, either for the M- or the P- atropisomer. The apparent reason was the low atropisomerization barrier due to the small steric demand of the ort o-substituents next to the biaryl axis. Probably for the same reason, extended NOE and ROE experiments, as successfully applied in other cases (Bringmann et al . , Magn . Reson . Chem . , 35 , 297-301 (1997)), did not give any diagnostically valuable long- range interactions between the naphthalene and the isoquinoline parts as expected for P- or M-configuration. First calculations (AMI) to determine the activation energy of the atropisomerization process confirmed the supposition of a rapid dynamic rotation about the biaryl axis at room temperature (ΔH' <20 kcal mol "1 ) . This assumption was further supported by low- temperature NMR experiments, leading to a clear decoalescence of the CH 3 -1 protons at ca . 220 K and a rough estimation of the atropisomerization barrier at this temperature as ca . 11 kcal mol "1 . Consequently, dioncophyllinol D has the absolute stereostructure shown in Figure 7, with all of the three stereocenters at C-1, C-3, and C-4 R- configured, whereas the axis is configuratively labile, leading to a rapid equilibrium of the P and M forms at room temperature. EXAMPLE 4 This example illustrates the partial and total syntheses of the following exemplary monomeric compounds of the present invention: 8-O-methyl-dioncophylline D, dioncophyllinol D, and 4 -oxodioncophylline D. In this example, approaches defined in previous disclosures are utilized in conjunction with known synthetic reactions and procedures, which can be found in Bringmann et al . , U.S. Patent No. 5,552,550; and Bringmann and Pokorny, The Alkaloids, Vol. 45 (G. Cordell, ed.), Academic Press, New York, pp. 127-271. Figure 8 schematically shows preparation of 8-0- methyl-dioncophylline D by partial synthesis from other related alkaloids by several alternative methods including: (a) from dioncophylline D; by N-formylation, selective 8-0-methylation and acid-catalyzed cleavage of the N-protective group ( analogous to : Bringmann et al . , Phytochemistry, 30 , 1691-1696 (1991)), (b) from dioncophyllinol D; by deoxygenation at C-4 to give dioncophylline D, and subsequent 8-0-methylation as above, or by N-beneylation , 8-0-methylation, and subsequent deoxygenation at C-4 ( analogous to : Bringmann et al., Phytochemi stry, 30 , 1691-1696 (1991)), and (c) from yaoundamine A (which may be isolated and purified from A . korupensis , or by deglycosylation from yaoundamine B which is isolable from the same plant) ; by trans-selective reduction ( analogous to : Bringmann et al., Angew. Chem . Int . Ed . Engl . , 25 , 913-915 (1986)), N- benzylation, and 6 -deoxygenation via the corresponding phenytetrazol- (or triflate-) derivative and hydrogenolytic debenzylation ( analogous to : Bringmann et al . , Phytochemistry, 31 , 4019-4024 (1992); Bringmann et al., Liebigs Ann . Chem . , 877-888 (1993)). Figures 9 and 10 schematically show two alternative methods of preparing dioncophylline D and 8-0- methyldioncophylline D by total synthesis, including: (a) (Figure 9) construction of the biaryl axis through intermolecular coupling of an appropriately protected and activated naphthalene building block 1 and a protected and activated tetrahydroisoquinoline part 2 using transition metal catalysis ( analogous to : Bringmann et al . , Heterocycles , 39, 503-512 (1994); Bringmann et al . , U.S. Patent No. 5,552,550) and subsequent cleavage of the protective groups, to give dioncophylline D, which may be converted to O-methyldioncophylline D as described above, and (b) (Figure 10) by construction of the biaryl axis using the "lactone method" ( analogous to : Bringmann et al . , Tetrahedron Lett . , 31 , 643-646 (1990)); Bringmann et al . , Methods of Organic Chemistry (G. Helmchen, et al . , eds.), Vol. E21a, Thierne, Stuttgart, 1995, pp. 567-587) comprising prefixation of an appropriately protected phenolic isoquinoline building block 4 with the acid chloride of the monocyclic benzoic acid derivative 3, transition metal catalyzed intramolecular coupling, ring cleavage with hydrogen transfer reagents, 8 -O-protection and oxidation to give the intermediate 6 whose aldehyde function is then used to build up the second naphthalene ring to give 7 ( analogous to : Bringmann et al . , Heterocycles , 39 , 503-512 (1994); Bringmann et al . , U.S. Patent No. 5,552,550), cleavage of the protective groups to give dioncophyllinone D, which can be transformed into 8-O-methyldioncophylline D as described above. Figure 11 shows a method for preparing dioncophyllinol D by partial synthesis from dioncophyllme D, by reduction with achiral (e.g., NaBH or chiral (e.g., S-BINAL-H) hydride transfer reagents ( analogous to : R. Noyori et al . , J. Am. Chem . Soc , 106, 6709-6716 (1984)), to give dioncophyllinol D or its epimer respectively. Figures 12-14 illustrate a method for preparing dioncophyllinol D and related 4 -hydroxylated naphthylisoquinoline alkaloids by total synthesis, comprising: (a) (Figure 12) synthesis of the required 4- hydroxyisoquinoline building block, e.g., with 3R- configuration, by stereoselective reductive ammation of the keto acetal 9 using the substituted 1- phenylethylamine 8 ( analogous to : Bringmann et al . , German Patent (D.O.S.) 38 19 438; Bringmann et al . , Liebigs Ann . Chem . , 795-805 (1990)) to give the ammo acetal intermediate 10, which can also be prepared by reductive ammation of the acetophenone 11 using the amino acetal 12, which, itself, is available by reductive amination of the aforementioned keto acetal 9 with unsubstituted 1-phenylethylamme (Bringmann and Geisler, Synthesis, 608-610 (1989); Bringmann et al . , German Patent (D.O.S.) 38 43 390; European Patent 0 374 647) or from the amino acid D-alanme ( analogous to : Jurcak and Golebiowski, Chem . Rev. , 89 , 149, (1989)); ring closure of 10 by Pommeranz-Fritsch cyclization to give 14, and Birch reduction for the elimination of the 7 -oxo- function to give 15 ( analogous to : Bringmann, The Alkaloids, Vol. 29 (A. Brossi, ed.) Academic Press, New York, 1986, pp. 141-184) which is the required building block for the synthesis of a series of 4 , 6 , 8-trihydroxy alkaloids with R-configuration at C-3 (the "Ancistrocladaceae/Dioncophyllaceae hybrid-type" alkaloids) , in particular 4-hydroxylated or 4 -oxo derivatives of korupensamines , ancistrobrevine C, ancistrobarterine A, and others; final reductive elimination of 0-6 using the tetrazol method ( analogous to : Bringmann et al . , Liebigs Ann . Chem . , 877-888 (1993)), 8-0-demethylation as before, and N-protection to give 16, the crucial building block for the C-4 hydroxyl, methoxy or oxo derivatives of dioncophyllines A-C, and the dioncophyllacines A-D; (b) (Figure 13) the corresponding enantiomeric isoquinoline building blocks, with 15, 3S-configuration, which can be prepared by the aforementioned methods, but starting from the enantiomeric materials, giving rise to ent-10 and thus ent-15, the synthetic precursor to lS-3S-configured 4 , 6, 8-trihydroxy alkaloids like 4 -hydroxylated or 4-oxo analogs of ancistrocladine, hamatine, 0- methylancistrocladine, and others ( "Ancistrocladaceae- type" alkaloids) and ent-16, the building block for IS, 3S-configured 4 , 8-dihydroxy alkaloids, such as 4- hydroxylated or 4-oxo analogs of dioncoline or 7-epi- dioncoline (inverse "Ancistrocladaceae/ Dioncophyllaceae hybrid-type" alkaloids - e.g., Bringmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed. ) , Academic Press, New York, 1995, pp. 127-271); (c) (Figure 14) the construction of the axis by intermolecular transition metal catalyzed coupling of the appropriately protected and activated naphthalene building block 1 ( analogous to : Bringmann et al . , Heterocycles , 39 , 503-512 (1994); Bringmann et al . , U.S. Patent No. 5,552,550) with the protected and appropriately activated isoquinoline building block 17 prepared from the aforementioned dihydroxytetrahydro- isoquinoline 16 by standard protection and activation steps and subsequent deprotection to give dioncophyllinol D ( analogous to : Viang et al . , J. Org. Chem . , 57 , 424-436 (1992)). Figures 15 and 16 illustrate methods of preparing an exemplary C-4 oxo compound of the present invention: dioncophyllinone D. These include by (a) (Figure 15) partial synthesis from isolated dioncophyllinol D through e.g., oxidation with Mn0 2 or (b) (Figure 15) starting from dioncophyllinol D obtained by total synthesis. Figure 16 illustrates preparation of dioncophyllinone D through independent total synthesis, by preparation of the appropriate 4 -oxo-tetrahydroisoquinoline building block by reductive ammation of the α-keto ester 21 with the appropriately substituted 1-phenylethylamme 22 to give the ammo ester 23 (which can likewise be produced by reductive ammation of the acetophenone 24 with the D- alanme derivative 25) , subsequent cyclization of 23 to give the 4 -oxo-tetrahydroisoquinoline 26, transformation into the building block 28, which is coupled to the aforementioned building block 1 (Brmgmann et al . , Heterocycles, 39, 503-512 (1994); Bringmann et al . , U.S. Patent No. 5,552,550), followed by hydrogenolytic and acid-catalyzed cleavage of the protective groups, to give dioncophyllinone D. EXAMPLE 5 Partial and Total Synthesis of Exemplary Dimeric Arylisoqumoline Alkaloid Compounds of the Present Invention: Homodimeric Naphthylisoquinoline Alkaloids, Heterodimeric Naphthylisoquinoline Alkaloids, and Heterodimeric Naphthylisoqumolme/Phenylisoqumolme alkaloids This example illustrates partial and total synthesis strategies for preparing exemplary homodimeric and heterodimeric arylisoqumoline alkaloids compounds of the present invention using approaches defined in previous disclosures and in conjunction with other now well-known reactions and procedures (Bringmann et al . , U.S. Patent No. 5,571,919; Bringmann et al . , U.S. Patent No. 5,578,729; Bringmann et al . , U.S. Patent Application No. 08/721,084; and Bringmann and Pokorny, The Alkaloids, Vol. 46 (G. Cordell, ed.), Academic Press, New York, 1995, 127-271. Figures 17 and 18 illustrate methods of preparing joziminol D (homodimeric dioncophyllinol D) 30 by partial (or total) synthesis, starting from natural (or synthetic) dioncophyllinol D. In the first scheme (Figure 17) dioncophyllinol D is N-formylated and then specifically O-acetylated to give N- formylated and O- acylated monomeric "halves" 29, followed by oxidative dimerization using silver oxide/triethylamine, and reduction of the central double bond using ΝaBH 4 /iPrOH and deprotection by refluxing in MeOH/HCl to give 30 ( analogous to : Bringmann et al . , Liebigs Ann . , 2045-2085 (1996); Bringmann et al . , Tetrahedron, 50 , 9643-9648 (1994)) . In the second scheme (Figure 18) dioncophyllinol D is subjected to N- and O-specific benzylation to give N- and O-benzylated monomeric "halves" 31, followed by oxidative dimerization using silver oxide/triethylamine and one- step reduction/deprotection by hydrogenation with H 2 /Pd/C, to give 30 ( analogous to : Bringmann et al . , Liebigs Ann . , 2045-2085 (1996) ) . Figures 19 and 20 illustrate a method for total synthesis of an exemplary heterodimeric arylisoquinoline alkaloid wherein one of the aryl groups is phenyl instead of naphthyl. In Figure 19, synthesis of the boronic acid activated building block 32 starts from 17, by lithiation with sec-BuLi, treatment with trimethylborate and quenching with water ( analogous to : Bringmann et al . , Liebigs Ann . , 2045-2085 (1996)), then synthesis of the protected monomeric building block 33 by transition metal catalyzed coupling of 32 with 35 (prepared from hydroquinone monoacetate 34 using trifluormethylsulfonyl chloride) to give 33 (Johnston, Chem . Ind . , 24 , 1000 (1982) ; and analogous to : Bringmann et al . , Liebigs Ann . , 2045-2085 (1996)). Synthesis of the activated building block 37 starts from 33, by selective bromination with tri -N-butyl ammonium tribromide and O-benzylation to give 36, and subsequent lithiation with sec-BuLi, and stannylation with tri -N-butylstannyl chloride ( analogous to : Bringmann et al . , Heterocycles , 39 , 503-512 (1994)) to give activated monomeric molecular "half" 37. Figure 20 illustrates the preparation of the second appropriately protected and activated monomer "half" (38) and the coupling of the two different monomers to give an exemplary heterodimeric arylisoquinoline alkaloid (39) comprising an exemplary naphthylisoquinoline alkaloid monomer (dioncophyllinol D) coupled to a representative phenylisoquinoline alkaloid monomer (phenylisoquinolin-4- ol) . In this scheme synthesis of the required building block 38 is accomplished by bromination of 29 with tri -N- butyl ammonium tribromide followed by O-protection with benzylbromide ; then transition metal catalyzed cross- coupling of 37 with 38, followed by deprotection by refluxing with MeOH/HCl then hydrogenation with H 2 /PdC to give 39 ( analogous to : Bringmann et al . , Heterocycles, 39 , 503-512 (1994); Bringmann et al . , U.S. Patent No. 5,552,550; Bringmann et al . , Liebigs Ann . , 2045-2085 (1996) ) . All of the references cited herein, including patents, patent applications, and publications, are hereby incorporated in their entireties by reference. While this invention has been described with an emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

Claims: WHAT IS CLAIMED IS; 1. A derivative of dioncophylline D, wherein the configuration at C-1 or C-3 is instead S; one or more phenolic hydroxyl group (s) is instead an ester, sulfonate ester, or ether group; a methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is instead an aromatic hydrogen substituent; the secondary amine site is instead an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is instead halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 is instead H; and/or the tetrahydroisoquinoline is instead a dihydroisoquinoline; with the proviso that said derivative is not ancistrobrevine A, 6-O-demethyl- ancistrobrevine A, yaoundamine A, yaoundamine B or ancistroheynine A. 2. A derivative according to claim 1, wherein the configuration at C-1 is S, one or more phenolic hydroxyl group (s) is instead an ester, sulfonate ester, or ether group; the methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is instead an aromatic hydrogen substituent; the secondary amine site is instead an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is instead halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and/or at least one CH 3 is instead H. 3. A derivative according to claim 1, wherein the configuration at C-3 is S, one or more phenolic hydroxyl group (s) is instead an ester, sulfonate ester, or ether group; the methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is instead an aromatic hydrogen substituent; the secondary amine site is instead an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is instead halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 is instead; H and/or the tetrahydroisoquinoline is instead a dihydroisoquinoline; with the proviso that said derivative is not ancistrobrevine A, 6-O-demethyl-ancistrobrevine A, yaoundamine A, yaoundamine B or ancistroheynine A. 4. A derivative according to claim 1, wherein the configuration at C-1 or C-3 is instead S; one or more phenolic hydroxyl group (s) is instead an ester, sulfonate ester, or ether group; a methyl ether group is instead a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) is instead an aromatic hydrogen substituent; the secondary amine site is instead an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof; one or more aromatic hydrogen substituent (s) is instead halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and/or at least one CH 3 is instead H; with the proviso that said derivative is not ancistrobrevine A or 6-O-demethyl-ancistrobrevine A. 5. A compound selected from the group consisting of derivatives of dioncophylline D, ancistrobrevine A, 6-0- demethyl -ancistrobrevine A, yaoundamine A, yaoundamine B, ancistroheynine A, dioncophylline B, dioncopeltine A, dioncophylline A, dioncophylline C, dioncolactone A, N- methyl -dioncophylline A, ancistrobrevine D, ancistrocladine, 5'-0-demethyl-8-0-methyl-7-epi- dioncophylline A, 5'-0-demethyl -7- epi-dioncophylline A, hamatine, ancistrobarterine A, 7 -epi -dioncophylline A, N- formyl ancistrocladine, N-methyl -ancistrocladine , 6- SUBSTTTUTE SHEET (RULE 26) deoxy- N-methyl -ancistrocladine, N- formyl -0, O-dimethyl - dioncophylline C, N- formyl -dioncophylline C, N- formyl-8 - O-benzyl -dioncophylline C, N- formyl -8 -O-methyl - dioncophylline C, N-formyl-8-0-pivaloyl-dioncophylline C, N- formyl- 8 -O-acetyl -dioncophylline C, N- formyl -8-0- benzoyl -dioncophylline C, and 8 -O-methyl -dioncophylline C, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be C.-Cg alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 may instead be H; the tetrahydroisoquinoline may instead be a dihydroisoquinoline; and (b) a substituent at C-4 is C.-Cg alkyl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano or oxo. 6. A compound according to claim 5, wherein said compound is selected from the group consisting of derivatives of dioncophylline D, ancistrobrevine A, 6-0- demethyl -ancistrobrevine A, yaoundamine A, yaoundamine B, and ancistroheynine A. 7. A compound according to claim 5, wherein said compound is selected from the group consisting of derivatives of dioncophylline C, N- formyl -O, O-dimethyl - dioncophylline C, N- formyl -dioncophylline C, N- formyl -8- O-benzyl -dioncophylline C, N- formyl -8 - O-methyl - dioncophylline C, N-formyl - 8 - O-pivaloyl -dioncophylline C, N- formyl - 8 - O-acetyl -dioncophylline C, N- formyl-8-0- benzoyl -dioncophylline C, and 8-O-methyl -dioncophyHine C. 8. A compound according to claim 5, wherein said compound is selected from the group consisting of derivatives of dioncophylline B, dioncopeltine A, dioncophylline A, dioncophylline C, dioncolactone A, N- methyl-dioncophylline A, ancistrobrevine D, and ancistrocladine . 9. A compound selected from the group consisting of derivatives of dioncophylline D, ancistrobrevine A, 6 - 0- demethyl-ancistrobrevine A, yaoundamine A, yaoundamine B, ancistroheynine A, dioncophyllacine A, dioncophyllacine B, dioncophylline B, dioncopeltine A, dioncophylline A, dioncophylline C, dioncolactone A, N-methyl - dioncophylline A, ancistrobrevine D, ancistrocladine, 5'- O-demethyl-8 -O-methyl -7- epi -dioncophylline A, 5'-0- demethyl-7-epi-dioncophylline A, dioncophylleine A, hamatine, ancistrobarterine A, 7 - epi-dioncophylline A, N- formyl ancistrocladine, N-methyl -ancistrocladine, 6- deoxy-N-methyl -ancistrocladine, N- formyl -O, O-dimethyl - dioncophylline C, N- formyl -dioncophylline C, N- formyl - 8 - O-benzyl -dioncophylline C, N- formyl -8 -O-methyl - dioncophylline C, N-formyl-8-O-pivaloyl-dioncophylline C, N- formyl- 8 -O-acetyl -dioncophylline C, N- formyl-8-O- benzoyl -dioncophylline C, and 8 -O-methyl -dioncophylline C, wherein: (a) the configurations at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (b) the isoquinoline is instead a fully aromatic isoquinoline; and (c) a substituent at C-4 is acyloxy, alkoxy, aryloxy, glycosyloxy or oxo; with the proviso that said compound is not dioncophyllacine A or dioncophyllacine B. 10. A compound according to claim 9, wherein said compound is selected from the group consisting of derivatives of dioncophylline D, ancistrobrevine A, 6 - 0- demethyl -ancistrobrevine A, yaoundamine A, yaoundamine B, ancistroheynine A. 11. A compound selected from the group consisting of derivatives of korupensamine A, korupensamine B, korupensamine C, korupensamine D, and ancistrobrevine B, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group (s) may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group (s) may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group (s) may instead be an aromatic hydrogen substituent; one or more secondary amine site(s) may instead be an amide, sulfonamide, tertiary amine, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amine site(s) may instead be a secondary amine; one or more aromatic hydrogen substituent (s) may instead be halo, nitro, amino, SUBSTTTUTE SHEET (RULE 26) hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and (b) a substituent at C-4 is C.-C 6 alkyl, halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano or oxo. 12. A compound selected from the group consisting of derivatives of korupensamine A, korupensamine B, korupensamine C, korupensamine D, and ancistrobrev e B, wherein: (a) the configuration at C-1 and C-3 may be the same or different, and each may be R or S; the configuration about the naphthalene/isoquinoline axis may be P or M, one or more phenolic hydroxyl group may instead be an ester, sulfonate ester, or ether group; one or more methyl ether group may instead be a phenolic hydroxyl group; one or more phenolic hydroxyl group may instead be an aromatic hydrogen substituent; one or more secondary amme site may instead be an amide, sulfonamide, tertiary amme, alkyl quaternary ammonium salt or corresponding Hoffmann elimination product thereof, one or more tertiary amme site may instead be a secondary amme; one or more aromatic hydrogen substituent may instead be alkyl, acyl, halo, nitro, ammo, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; at least one CH 3 may instead be H; the tetrahydroisoquinoline may instead be a dihydroisoqumolme or a fully aromatic isoquinoline; (b) a substituent at C-4 is acyloxy, alkoxy, aryloxy, glycosyloxy or oxo; and (c) at least one aromatic hydrogen substituent is instead an acyl or C.-Cg alkyl, and/or a substituent at C-2' is not methyl when C-1 and C- 3 are each substituted with a methyl. 13. A dimeric arylisoqumoline comprising coupled first and second arylisoqumoline monomers, wherein at least one of said arylisoqumoline monomers is an arylisoqu oline radical of a compound of claim 1. 14. A dimeric arylisoqumoline comprising coupled first and second arylisoqumoline alkaloid monomers, wherein at least one of said arylisoqumoline monomers is an arylisoqumoline radical of a compound of claim 5. 15. A dimeric arylisoqumoline comprising coupled first and second arylisoqumoline alkaloid monomers, wherein at least one of said arylisoqumoline monomers is an arylisoqu oline radical of a compound of claim 9. 16. A dimeric arylisoqumoline comprising coupled first and second arylisoqumoline alkaloid monomers, wherein at least one of said arylisoqumoline monomers is an arylisoqumoline radical of a compound of claim 11. 17. A dimeric arylisoqumoline comprising coupled first and second arylisoqumoline alkaloid monomers, wherein at least one of said arylisoqu oline monomers is an arylisoqumoline radical of a compound of claim 12. 18. A compound of the formula: OR SERIES III wherein : (a) A or B is C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together are =0, =S, or -0(CH 2 ) n 0-, wherein n is an integer from 2-4; (b) R 2 is H, C.-C 8 alkyl, an amide, or sulfonamide ; (c) R 1 and R 3 may be the same or different and each may be —- H, ' H, —- CH 3 , or CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or C.-C 6 alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and (g) R 7 is selected from the group consisting of H, C--C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol, cyano, and an arylisoquinoline of the formula: ARYLISOQUINOLINE I OR ARYLISOQUINOLINE II OR ARYLISOQUINOLINE III wherein : (a) A or B is C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together are H, =0, =S, or -0(CH 2 ) n 0-, wherein n is an integer from 2-4; (b) R 2 is H, C.-Cg alkyl, an amide, or sulfonamide ; (c) R 1 and R 3 may be the same or different and each may be —— H, H, — CH 3 , or CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or C^C g alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; and (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring . 19 . A dimeric arylisoquinoline of the formula : SERIES II OR SERIES III wherein : (a) A or B is C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together are =0, =S, or -0(CH 2 ) n 0-, wherein n is an integer from 2-4; (b) R 2 is H, alkyl, an amide, or sulfonamide; (c) R 1 and R 3 may be the same or different and each may be — H, H, — CH 3 , or ' CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or C- L -Cg alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano ; (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and (g) R 7 is an arylisoquinoline radical of a compound of claim 1. 20. A dimeric arylisoquinoline of the formula: SERIES I OR SERIES II OR SERIES III wherein : (a) A or B is C.-C 6 alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, Ξ glycosyloxy, thiol or cyano; or A and B together are =0, =S, or -0(CH 2 ) n 0-, wherein n is an integer from 2-4; (b) R 2 is H, C 1 -C & alkyl, an amide, or sulfonamide; (c) R 1 and R 3 may be the same or different and 0 each may be —- H, ' H, "— CH 3 , or "CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or C.-C 6 alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be alkyl, acyl, halo, 5 nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and 0 (g) R 7 is an arylisoquinoline radical of a compound of claim 5. 21. A dimeric arylisoquinoline of the formula: SERIES I OR OR SERIES III wherein: (a) A or B is C j -Cg alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together are =0, =S, or -0 (CH 2 ) n 0- , wherein n is an integer from 2-4; (b) R 2 is H, C.-C 6 alkyl, an amide, or sulfonamide ; (c) R 1 and R 3 may be the same or different and each may be —- H, ' H, —"CH 3 , or ' CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or C--C 6 alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be C--C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and (g) R 7 is an arylisoquinoline radical of a compound of claim 9. 22. A dimeric arylisoquinoline of the formula: SERIES I OR OR SERIES III wherein: (a) A or B is alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together are =0, =S, or -0(CH 2 ) n 0-, wherein n is an integer from 2-4; (b) R 2 is H, C.-C 8 alkyl, an amide, or sulfonamide; (c) R 1 and R 3 may be the same or different and each may be — — H, H, — ■ CH 3 , or CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or C.-C 6 alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and (g) R 7 is an arylisoquinoline radical of a compound of claim 11. 23. A dimeric arylisoquinoline of the formula: SERIES I OR OR SERIES III wherein: (a) A or B is alkyl, acyl, aryl, halo, nitro, amino, azido, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; or A and B together are =0, =S, or -0(CH 2 ) n 0-, wherein n is an integer from 2-4; (b) R 2 is H, C.-Cg alkyl, an amide, or sulfonamide; (c) R 1 and R 3 may be the same or different and each may be — H, H, — CH 3 , or CH 3 ; (d) R 5 , R 6 , and R 8 may be the same or different and each may be H or alkyl; (e) one or more aromatic hydrogen substituent (s) may instead be C.-C 6 alkyl, acyl, halo, nitro, amino, hydroxyl, acyloxy, alkoxy, aryloxy, glycosyloxy, thiol or cyano; (f) the tetrahydroisoquinoline ring may instead be a dihydroisoquinoline ring or a fully saturated isoquinoline ring; and (g) R 7 is an arylisoquinoline radical of a compound of claim 12 .

Inventors: BOYD MICHAEL R, BRINGMANN GERHARD, WENZEL MATTHIAS, BOYD, MICHAEL, R., BRINGMANN, GERHARD, WENZEL, MATTHIAS
Applicants: US HEALTH, THE GOVERNMENT OF THE UNITED STATES OF AMERICA, R EPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Application year: 1998
Main classification: C07D217
IPC codes: C07D217, C07D491