Anticancer agent alkaloids

Other anticancer agents have distinct mechanisms paclitaxel and its relatives target microtubules as do the vinca alkaloids. Antiestrogens and antiandrogens target estrogen and androgen receptors. 

Vinblastine (4) and vincristine (5) are closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus roseus (L.) G. Don (formerly known as Vinca rosea L.), the Madagascar periwinkle. Both of these anticancer agents, known as vinca alkaloids in the medical literature, are specific binders of tubulin, leading to tubulin depolymerization and cell cycle arrest in the metaphase stage. 

The Catharanthus (Vincd) alkaloids, vinblastine (4) and vincristine (5), are not only very useful anticancer agents, but are also bona fide lead compounds. A semisynthetic vinblastine (4) analogue, vinorelbine (52) is indicated for lung and mammary carcinomas. Vinflunine was further developed from vinorelbine, and has shown promise in phase II clinical trials. >93... 

Until now, this relatively new class of imidazo[4,5-fl]pyrrolo[3,4-c]carbazole alkaloids includes only three natural products. These natural products showed G2 check point inhibitor activity, and thus represent a promising target for the development of new chemotherapeutic anticancer agents. Due to this fact, a wide range of analogs of imidazo[4,5-fl]pyrrolo[3,4-c]carbazole alkaloids were reported for structure activity studies. 

One particular example of the early extraction of a chemical from a plant, a small tree found in the rainforests of eastern Queensland, would be that of acronycine 1 [1,2], an alkaloid currently undergoing clinical trials as an anticancer agent. More recently, a group in Perth at Murdoch University succeeded in extracting the alkaloid, swainsonine 2 from a desert shrub which causes poisoning in cattle [3]. Swainsonine has been found to exhibit an interesting spectrum of biological activity [4], especially as a potent, reversible inhibitor of various a-D-mannosidases [5]. 

The answer is c. (Hardman, pp 1260-1262.) Paclitaxel is a large structural molecule that contains a 15-membered taxane ring system. This anticancer agent is an alkaloid derived from the bark of the Pacific yew tree. Its chemotherapeutic action is related to the microtubules in the cell. Paclitaxel promotes microtubule assembly from dimers and causes microtubule stabilization by preventing depolymerization. As a consequence of these actions, the microtubules form disorganized bundles, which decreases... 

In the anticancer area, the use of natural products as direct agents or as novel lead compounds for the generation of synthetic or semisynthetic analogs has proved remarkably productive, and a recent survey showed that 62% of new anticancer agents over the last 10 years have been natural products or agents based on natural product models.7 Examples of clinically important plant-derived natural products are the vinca alkaloids vinblastine (4) and vincristine (5), the podophyllotoxin analogs etoposide (6) and teniposide (7), the diterpenoid paclitaxel (Taxol ) (8), and the camptothedn-derivative topotecan (9). 

More recently, the radical cyclization onto azide groups pioneered by Kim was applied in the construction of the B/E spirocyclic junction found in the [6.5.6.5] ABCE ring system of indole alkaloids such as strychnine, the clinically used anticancer agents vincristine and vinblastine and, in particular, aspidospermine87. In model system studies, cyclization of the iodoazide 24, prepared in 6 steps, in the presence of (TMS SiH, produced the N—Si (TMS>3 protected alkaloid 25, that after washing with dilute acid afforded the amine 26 in 95% yield from 24 (equation 58). The formation of the liable N—Si(TMS)3 bond was considered to arise from the reaction of the product amine 26 with the byproduct (TMS)3SiI. 

Vincristine, a vinca-alkaloid, prevents proliferation of tumor cells through the inhibition of tubulin polymerization. Vincristine is used as an anticancer agent for leukemia and lymphoma (Himes etal, 1976 Owellen etal., 1976). Clinical use of vincristine is often limited by its adverse effects, which include painful peripheral neuropathy (i.e., neuropathic pain) (Casey et al., 1973 Sandler et al., 1969). Elucidation of the detailed mechanism of neuropathic pain caused by vincristine is needed to improve quality-of-life for patients, and to make vincristine more tolerable for cancer treatment. 

Vinblastine (4 in Chart 1) and its congeners are dimeric indole alkaloids derived from Catharanthus (Vinca) roseus. Nowadays, the vinca alkaloids constitute an important class of widely and successfully used anticancer agents that inhibit tubulin polymerization [8],... 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

A variety of plant substances with planar, polycyclic, aromatic structures can intercalate with DNA, examples being the quinoline alkaloid camptothecin and the furanocoumarin phenolic psoralen (Table 12.1). A variety of plant-derived anthraquinones and naphthoquinones bind to DNA and it is notable that the structurally related anthraquinones mitox-antrone and adriamycin are clinically employed as anticancer drugs (Table 12.1). DNA-binding compounds that interfere with DNA repair, DNA replication and gene expression are cytotoxic and have potential as anticancer agents (see Chapter 9). 

Arisawa M, Kinghom AD, Cordell GA, Farnsworth NR (1983) Plant Anticancer Agents. XXIV. Alkaloid Constituents of Simaba multiflora. J Nat Prod 46 222... 

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