Cytotoxic alkaloids

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Xylopine Acridone alkaloids Cytotoxic to A-549, HCT-8, KB, P388 cells — 295... 

Hydroxyglucopiericidin A [9], which possesses a terminal OH moiety and a glucose moiety at the C-10 position, was isolated from the fermentation broth of Streptomyces OM-5689 as an alkaloid cytotoxic to B16 melanoma cells. 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

In addition to the Vinca alkaloids and taxol, a limited number of other cytotoxic agents have been demonstrated to act at the level of tubulin. This... 

The phenanthroindolizidine alkaloid (-)-antofine (95) exhibits high cytotoxicity to drug-sensitive and multidrug-resistant cancer cells by arresting the G2/M phase of the cell cycle. In the first asymmetric total synthesis of (-)-95, the late-stage construction of pyrrolidine 94 for the final Pictet-Spengler cyclo-methylenation to 95 was performed by RCM and subsequent hydrogenation (Scheme 18) [67]. 

A cytotoxic alkaloid has been isolated from the filamentous species Hapalosi-phon forUinalis strain V-3-1. This isolate was made from soil samples collected in the Marshall Islands in 1981. This strain produces the lipophilic compound hapalindole A, which has a broad range of antialgal and antimycotic activity (9). OscUlatoria acutissima strain B-1, isolated from a freshwater pond in Oahu, was found to produce two novel macrolide compounds termed acutiphycin and 20, 21-didehydroacutiphycin. These macrolides show cytotoxicity (KB and NIH/3T3) and antitumor activity (Murine Lewis lung carcinoma) (10). 

Pang L, Hoult JR (1997) Cytotoxicity to macrophages of tetrandrine, an antisUicosis alkaloid, accompanied by an overproduction of prostaglandins. Biochem Pharmacol 53(6) 773-782... 

Haliclonacyclamine F (25), arenosclerin D (26), and arenosclerin E (27) have been recently isolated from the sponge Pachychalina alcaloidifera endemic in Brazil [26]. The alkaloids 25-27 were isolated from the cytotoxic, antibiotic, and antituberculosis MeOH crude extract of P. alcaloidifera by a series of separations on silica-gel and cyanopropyl-bonded silica-gel columns. The structures of compounds 25-27 were established by the same approach employed for the structural elucidation of haliclonacyclamine E (13) and arenosclerins A-C (14-16) [18], as well as by comparison with NMR data for this last series of alkaloids. The alkaloids 25-27 displayed moderate cytotoxic activity against SF295 (human CNS), MDA-MB435 (human breast), HCT8 (colon), and HL60 (leukemia) cancer cell lines. 

Indole alkaloids Strychnos icaja roots SiOj Hx + CHCI3 + MeOH + HjO AcOEt + iPrOH + NH3 aqueous DragendorlTs reagent UV Antimalarial, cytotoxic activity 14... 

There are numerous examples of intramolecular Heck reactions,151 such as in Entries 10 to 14. Entry 11 is part of a synthesis of the antitumor agent camptothecin. The Heck reaction gives an 11 1 endocyclic-exocyclic mixture. Entries 12-14 are also steps in syntheses of biologically active substances. Entry 12 is part of a synthesis of maritidine, an alkaloid with cytotoxic properties the reaction in Entry 13 is on a route to galanthamine, a potential candidate for treatment of Alzheimer s disease and Entry 14 is a key step in the synthesis of a potent antitumor agent isolated from a marine organism. 

Hoet S, Stevigny C, Block S, et al. Alkaloids from Cassytha filiformis and related apor-phines anti-trypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases. Planta Med 2004 70 407-413. 

Examples of inhibitors of chromatin function derived from flowering plants (Fig. 80) are etoposide (lignan) and alkaloids camptothecin, Vinca alkaloids, and 7 epitaxol. The rhizome of Podophyllum peltatum L. (May apple, Berberidaceae) has been used to remove warts and to relieve the bowels from costiveness since very early times. It contains podophyllo-toxin, a cytotoxic lignan from which etoposide (Vepesid ), which is used to treat lung cancer, lymphomas, and leukemias on account of its ability to inhibit the activity of... 

In regard to the antineoplastic properties of Rutaceae, this family has attracted a great deal of interest for its ability to elaborate series of cytotoxic benzo[c]phenanthri-dine and acridin alkaloids. Examples of acridin alkaloid are pyrano-acridone and acronycine characterized from Acronychia baueri Scott. 

Dassonneville L, Lansiaux A, Wattez N, et al. Cytotoxicity and cell cycle effects of the plant alkaloids cryptolepine and neocryptolepine relation to drug-induced apoptosis. J Nat Prod 2001 64 134-135. 

The pyrrolonaphthyridines 208 and 209 can be prepared from rearrangement of the pentacycle 207 upon treatment with trifluoroacetic acid (TFA) (Scheme 52). These products are of interest as they have the same structural skeleton as the indole alkaloid (—)-goniomitine, isolated from the root bark of Gonioma Malagasy <1995JOC3282>. Compound 208 has since been used in the synthesis of further derivatives which show cytotoxic activity against leukemia cells <2001BML79>. 

Two new polycyclic pyridoacridine alkaloids, arnoamine B, 289, and its demethylated analogue, arnoamine A, have been isolated from the ascidian Cystodytes sp. These new compounds are the first known examples of pyrroles fused to pyridoacridines, have antifungal properties, and are cytotoxic in several human tumor cell lines <1998JOC1657>. Both these compounds have been synthesized, starting from the hydrazone 290 with a Fischer indole synthesis (Scheme 73) <2000JOC5476>. 

Tetracyclic /3-carboline alkaloids, known as canthines, have a peri-fused indolo[3,2,Tnaphthyridine structure. Over 40 members of this class of compound have been isolated, and they are of interest on account of their broad range of pharmacological effects (antimicrobial, cytotoxic, antibacterial, anticancer). 

Canthin-6-one, which is a cytotoxic alkaloid, is synthesized in six steps from harmalane (Scheme 84) <1999TL7075>. The second step is a [4+2] cycloaddition with methyl 2-(dimethylamino)acrylate under singleelectron-transfer electrolysis. 

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