Vincristine oxidation

Vincristine may also be prepared in a semisynthetic process starting from vinblastine. Vinblastine or a salt thereof, preferably the sulfate, is oxidized with chromic acid or with one of its salts at a low temperature, the reaction mixture is neutralized or rendered alkaline and the product is separated therefrom by extraction, the extract is evaporated to dryness, the dry residue is optionally formylated, vincristine, and optionally N-demethylvinblastine also, are Isolated from the product, and the product(s) are optionally converted into their salts preferably into the sulfates, according to U.S. Patent 3,899,493. 

The extremely low yield of vincristine (2) from intact plants has made pursuit of its biosynthesis a very challenging problem, which at this point in time remains unsolved. Kutney et al. have used both anhydrovinblastine (8) (227) and catharanthine N-oxide (107) (233) as precursors to vincristine (2) in a cell-free preparation, but incorporation levels were extremely low. Therefore, the question of whether vinblastine (1) is an in vivo, as well as an in vitro, precursor remains to be answered. Several possibilities exist for the overall oxidation of vinblastine (1) to vincristine (2), including a direct oxidation of the A-methyl group or oxidative loss of the N-methyl group followed by N-formylation. 

As a substrate for chemical modification, vincristine (2) represents much more challenge. The extracted yield of 2 from Catharanthus is approximately 10% that of 1, making this compound a much scarcer substrate (42). Furthermore, the chemical lability of the N-1 formyl bond is extreme under a variety of conditions. The preparation of compounds in this series is usually accomplished by performing the requisite functional group interconversions with compounds bearing an N-1 methyl and reserving the oxidation of this methyl for the last step. 

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... 

Pharmacokinetics Intravenous injection of vincristine or vinblastine leads to rapid cytotoxic effects and cell destruction. This in turn can cause hyperuricemia due to the oxidation of purines to uric acid. The hyperuricemia is ameliorated by administration of the xanthine oxidase inhibitor, allopurinol (see p. 417). The agents are concentrated and metabolized in the liver and are excreted into bile and feces. Doses must be modified in patients with impaired hepatic function or biliary obstruction. 

If the C-15, C-16 bond is oxidatively cleaved, the secodine skeleton results (the proposed progenitor of the Aspidosperma and the iboga systems) through alternative Diels-Alder type cyclizations to afford tabersonine and catharanthine. The bisindole alkaloids of Catharanthus roseus reflect the union of vindoline and catharanthine to afford anhydrovinblastine modification affords the clinically significant alkaloids, vinblastine (VLB) and vincristine (VCR Fig. 39). The alkaloids, particularly VCR, are important as anticancer agents and have led to the development of the semisynthetic derivatives vindesine and vinorelbine (Fig. 40). Synthetic approaches are available to join the monomeric precursors. The enzymatically controlled sequence of reactions from tabersonine to vindoline has been elucidated. 

This reaction has been extensively studied in the case of the chlopromazine radical (R -mediated aminopyrine (S) oxidation [41], a typical reaction for xenobiotics, as well as in the case of the vindoline radical (R -mediated catharanthine (S) oxidation [42], a key reaction in the biosynthesis of the anticancer drugs, vinblastine and vincristine, which are obtained from Catharanthus roseus. 

The participation of peroxidase in the metabolism of alkaloids has frequently been described in the literature [42,50,52,150,151], However, the participation of peroxidase in alkaloid metabolism is generally associated with alkaloid turnover and catabolism, which generally reduces the biological (pharmacological) activity of such compounds [152-154]. This is the case of the oxidation of vincristine (XLV) by peroxidase to lead to N-formyl-catharinine (XLVI) [154] (Scheme XXIII). 

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. 

Another enzyme that has been implicated in the metabolism of vincristine in acute myeloblastic leukaemia (AML) cells is myeloperoxidase. The fact that AML is resistant to vincristine has been related to the presence of mieloperoxidase, which is able to catalize the vincristine s oxidative breakdown [198, 199]. 

The use of Na-formyl compounds such as vincristine in cancer therapy has stimulated numerous attempts during the past few years to prepare other iVa-formyl compounds by oxidation of natural or synthetic relatives of vinblastine, usually by means of chromic acid. The use of a large excess of Jones reagent at -78 °C is reported to give particularly satisfactory results. Thus, anhydrovin-blastine (255) gives an 80% yield of the related Na-formyl derivative other examples of the use of this oxidant are also cited. ... 

It was previously known that oxidation of vinblastine sulfate with chromyl acetate leads to vincristine 471). Szantay and coworkers have found that a similar oxidation carried out on the free base 665 led instead to the cyclic derivative, 756, in which the original velbanamine part has undergone a 3, 7 -transannular cyclization into a i/ -aspidosperma-type skeleton. Similar oxidation of vincristine (666) led to the corresponding cyclized product 757. Acid treatment of the cyclized derivatives resulted in an aspidospermane- eburnane skeletal rearrangement leading to novel bisindoles with the i/ -eburnea-aspidosperma-type skeleton, e.g., 756 758 472). 

Vincristine was oxidized to the ring-cleavage product, V-formylcatharinine... 

Natural products have a history of providing novel, clinically useful anticancer drugs and a number of these have come from higher plants (ref. 1-21). In addition, many of these compounds have served as prototypes for the development of novel analogs of clinical importance. Some specific examples are colchicine (ref. 22) and its derivatives, the podophyllotoxins (ref. 23) including the clinically-effective epipodophyllotoxin derivatives etoposide and teniposide (ref. 24), and the Vinca alkaloids, vincristine, vinblastine, and vindesine (ref. 25,26). More recently indicine N-oxide, homoharringtonine and taxol have entered clinical trials (ref. 13,21). The discovery of natural products with potential as anticancer drugs has recently been reemphasized by the NCI. 

Vincristine (VCR) was isolated as a minor alkaloid from the leaves of the Madagascan periwinkle, in which the vindoline N-methyl group is oxidized to an iV-formyl moiety. The isolation of vincristine was reported in 1961 [7] and the chemical structure, including stereochemistry, was reported at almost the same time as that ofVLB [4]. 

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