Vincristine 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. 

Vincaleukoblastine (186) and vincristine [leurocristine (187)] are two pharmaceutically important antitumor alkaloids of the vindoline-... 

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 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 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. 

Multiple single-point modification of both halves of the bisindole framework provided vinepidine (144), a bisindole alkaloid that exhibited experimental antitumor activity similar to vincristine without demonstrating the acute neuronal toxicity of this alkaloid. Ultimately, the vinepidine experience was both educational and an exercise in humility, since the compound showed promise in preclinical neurotoxicology models yet demonstrated considerable neurotoxicity in clinical trials. Nevertheless, vinepidine brings a rich example of the combined effects of ring D conformation (with its associated effect on N-6 basicity) and the presence of an N-1 formyl group. 

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... 

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). 

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. 

Alkaloids are among the most important groups of antitumor compounds that have been studied (Cordell, 1978,1981 Suffness and Cordell, 1985). Vincristine and vinblastine, from Catharanthus roseus (periwinkle, Apocynaceae), are used in the treatment of leukemia. 

Numerous bisindole alkaloids, formed by dimerization of monomeric monoterpenoid-derived indoles, have been isolated. Probably the best source of these alkaloids is Cathara-nthus roseus bisindole alkaloids from this source have been tabulated (Blasko and Cordell, 1990). Several of these alkaloids antitumor activity (Blasko and Cordell, 1988) most important in this regard are vincristine (55) and vinblastine (56) from Catharanthus roseus (Fig. 34.15). Certain other dimeric indole alkaloids known as curares have paralytic effects in animals (see the subsection Curares from Strychnos species, above). 

Taxol (42) is highly cytotoxic and has broad antitumor activity. This alkaloid acts by a mechanism different than any other antitumor drug. At concentrations completely inhibitory to cell division, taxol had no significant effects on DNA, RNA, or protein synthesis, but HeLa cells were blocked in late G2 and/or M phase. In contrast to other antimitotic agents such as colchicine, maytansine, vincristine, or podophyllotoxin, taxol (42) was found to promote assembly of calf-brain microtubules, and the microtubules so produced were resistant to depolymerization by cold or CaCl2. 

In addition to the anticancer indole alkaloids vinblastine and vincristine, discnssed in the next section, many indoles display antitumor activity. Space does not allow complete coverage of these smdies. Indole-3-carbinol (Scheme 12, 75), found in vegetables of genns Brassica (kale, cauliflower, broccoli, turnip, collard, and others), its acid- and/or enzymatic-induced dimer, 3,3 -diindolylmethane (76), and its trimer, 2-(indol-3-yhnethyl)-3,3 -diindolylmethane (77), inhibit cancer cell proliferation and induce apoptosis in several cell lines [88-91]. However, one study reports that... 

Different chemotherapeutic dmgs currently used to treat cancer patients are alkaloids like vincristine and vinblastine or taxanes paclitaxel and docetaxel. Although berberine is still not used in a clinical setting, it also possesses antitumoral activity against a number of tumor types. Indeed, a study using 60 tumor cell lines showed that the IC50 value for berberine was similar to that of other alkaloids used in chemotherapy like paclitaxel or vinblastine [120]. Moreover, in contrast to other antitumoral drugs, the secondary toxicity of berberine is very low as explained in... 

Formation of Alkaloids in Cell-Suspension Cultures.- This subject has been an active area of research in the last few years, and it is potentially a way to obtain economically useful natural products in a controlled environment, rather than by extracting whole plants, which are often difficult to cultivate in hospitable regions of our planet. Several books on this topic have appeared. The species Catharanthus roaeus has attracted much attention since it is a source of the clinically useful antitumor agents vinblastine and vincristine. Extensive work with this species has been carried out by Zenk ,Kutney ,Scott ,and their... 

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