Vinblastine antitumor alkaloids

The antitumor alkaloids vinblastine (1) and vincristine (2) were the first natural products to be used on a large scale as anticancer agents, and they thus blazed the trail for others that came afterward. Vinblastine (as vincaleukoblastine) was isolated from Catharanthus roseus (L.) G. Don, which was formerly known... 

The Polonovski reaction (see Volume 6, Chapter 4.7) — the action of an acid anhydride on an V-oxide — can give rise both to elimination or fragmentation reactions. Potier has modified the fragmentation by use of TFAA rather than AC2O and has applied this version to a useful synthesis of compounds related to antitumor alkaloids of Catharanthus roseus, e.g. vinblastine and vincristine. 

Vinblastine Sulfate, USP. Vinblastine sulfate. Vcihun. vincaleucohlastinc. VLB. NSC-49842, is an antitumor alkaloid isolated from Vim ti rosea L.. the periwinkle plant. It is soluble in water and alcohol. Vials containing 10 mg of vinblastine sulfate as a lyophili/cd plug are supplied. It is reconstituted by the addition of sodium chloride solution for injection preserved with phenol or benzyl alcohol. 

Higher plants have evolved an extraordinary variety of secondary metabolic pathways, the resulting products of which have been put to use by man providing pharmaceuticals for drug use, insecticides and various allelochemicals for pest control, and extracts for the flavor and fragrances industries. In spite of advances in synthetic organic chemistry, plants remain a major source of natural products, particularly in the specialty chemicals industry. Compounds, such as the insecticide derived from Azadiraohta indioa or the antitumor alkaloids vinblastine and vincristine found in periwinkle (Catharanthus roseus) (1 ), have complicated structures which preclude at the present time the development of an economical chemical synthesis (Figure 1). In the case of... 

The antibiotic griseoviridin (60) has been mentioned (see Section 9.27.3.3). The antitumor alkaloid vinblastine (411) (from Vinca rosea) is used widely in the treatment of Hodgkin s disease <89CC518>. The dibenz[(//]azonine alkaloids neodihydrothebaine (412 R = OMe, = H) and bractazonine (412 R = H, R = OMe) have been isolated from Papaver bracteatum <84H(22)2007> (see also... 

The blogenetically modeled synthesis of minovine (2) and ajmaline (8) has been reported. Both velbanamlne (10), a degradation product of the antitumor alkaloids vinblastine and vincristine, and catharanthlne were constructed from the same lactam intermediate (9). 

The vinblastine alkaloids are important chemotherapeutic materials, and are well known for their antitumor properties. A two-electron oxidation of alkaloid cantha-ranthine (125) followed by nucleophilic capture of the resulting imminium ion (126) by Cio of vindoline (127), afforded (128) and provided access to this important class of materials (Scheme 29) [56]. 

The functionality associated with N-1 of the vindoline portion of the bisindole alkaloids confers much biological diversity to these compounds. This property is exemplified by the differences in the cellular pharmacology, antitumor efficacy, and toxicity of vinblastine (1) and vincristine (2). Since 1 is isolated from extracts of Catharanthus in approximately 10-fold greater yield, it is not surprising that several oxidative methods have... 

The 4-acyl derivatives of 4-deacetylvinblastine (98) are among the earliest semi-synthetic compounds prepared in exploring the medicinal chemistry of the bisindole alkaloids from Catharanthus. By 1965, the clinical utility of vinblastine (1) and vincristine (2) was firmly established, and the naturally occurring congeners leurosine (3) and leurosidine (4) had been well characterized with respect to their experimental antitumor activity. Since these compounds were substantially less active in animal tumor... 

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

Streptoverticillium album K-25l/ the antitumoral bis-indole alkaloids vinblastine and vincristine/ verruculogen, a very potent mycotoxin produced by several Penicillium species and melatonin, a hormone found in all living creatures from algae to humans, just to mention the most important ones. 

Due to their interesting complex structure and biological activity, indole alkaloids such as strychnine (254), vindorosine (255) and vindoline (256) have attracted considerable attention. Vindoline is a key component in the preparation of the antitumor drugs vincristine and vinblastine (10) [17-19,179-183]. These alkaloids include the same tetracyclic core 257 known... 

Baxster RI, Dorschel CA, Lee SL, Scott AI. Biosynthesis of the antitumor cafiiaranfiius alkaloids. Conversion of anhydrovinblastine into vinblastine. J. Chem. Soc. Chem. Comm. 1979 257-259. Gueritte F, Bac NV, Langlois Y, Potier P. Biosynthesis of antitumour alkaloids from Cafiiaranfiius roseus. Conversion of 20 deoxyleurosidine into vinblastine. J. Chem. Soc. Chem. Comm. 1980 452-453. 

All four vinca alkaloids block mitosis with metaphase arrest. Their antitumor activity is based on their high binding affinity to intracellular tubulin, which is the protein subunit of the spindle microtubules. The binding constants of vincristine, vinblastine, and vindesine for tubulin are 8, 6, and 3.3 nmol/1 respectively (9,10). The formation of complexes between the vinca alkaloids and tubulin prevents the polymerization of the tubulin subunits to microtubules, which results in depolymerization of microtubules and inhibition of microtubule assembly. Based on the fact that microtubule assemblies also play a pivotal role in the movement of neurotransmitter substances along neuronal axons, vinca alkaloids can cause neurotoxicity, particularly at higher concentrations (9,10). 

The vinblastine alkaloids are important chemotherapeutic materials, and are well known for their antitumor properties. A two-electron electrooxidation of alkaloid cantharanthine (74), followed by nucleophilic capture of the resulting imminium ion 75 by Cjo of vindoline (76), affords 77 and provides access to this important class of materials [21], Oxidation of cantharanthine (74) was carried out in the presence of vindoline (76) at a potential that allowed the selective oxidation of the former. Oxidation was shown to occur in a stepwise manner with vindoline (76) serving to intercept the putative dication 75, and leading to the production of 77. Reduction of the latter with sodium borohydride afforded anhydrovinblastine (78) in a 52% yield accompanied by 12% of the material epimeric at C]. ... 

A group of mitotic inhibitors (vinblastine, vincristine, and vinorelbine) exert their cytotoxic effects by binding to tubulin. This inhibits formation of microtubules, causing metaphase arrest. Their mechanism of action and metabolism are similar, but the antitumor spectrum, dose and clinical toxicities of vinblastine, vincristine, and vinorelbine are very different. Paclitaxel and docetaxel are also mitotic inhibitors. However, they differ from the vinca alkaloids by enhancing microtubule formation. As a result, a stable and nonfunctional microtubule is produced. 

Although not listed in the tables, at least four other natural product drugs have given yeoman service in the antitumor area. The first of these is paclitaxel (Taxol ) which sold US 1.6 billion in 2000 this is followed by the vinca alkaloids vinblastine and vincristine. Completing the quartet are the natural product-derived epi-podophyllotoxin derivatives teniposide and etoposide and the materials derived from camptothecin, topotecan and CPT-11. These will probably not be the only natural product drugs in the antitumor field, as can be seen by inspection of Table 6.3, where Cragg and Newman recently reported on the source... 

Some tumors become resistant to several classes of antitumor agents, even if they have never been exposed to some of these agents. This is called multidrug (or pleiotropic drug) resistance. Drugs to which these cells become resistant include antibiotics, colchicine, the vinca alkaloids (vincristine vinblastine) and epidophyllotoxins (VP-16). These agents do not share a common mechanism of action. 

Vinblastine (117) and vincristine, well-known antitumor bisindole alkaloids, are biogeneticaUy derived from the coupling of vindoHne (123, Aspi-dospema type) and catharanthine (124, Iboga type). Recent progress (since a comprehensive review by Kam and Choo ) on the chemistry of these alkaloids is described in this section. 

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