Alkaloids Catharanthus

W. I. Taylor and N. R. Famswortli, eds., The Catharanthus Alkaloids, Botanj, Chemist, Pharmacology and Clinical Uses, Marcel Dekker, New York, 1973 W. I. Taylor and N. R. Famswortli, eds.. The Uinca Alkaloids, Botanj, Chemistry and Pharmacology, Marcel Dekker, New York, 1973. 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Scheme 20. Structures of dimeric Catharanthus alkaloids and their microbial or enzymatic transformation products.

W.I. Taylor and N. R. Farnsworth, eds., Catharanthus Alkaloids Botany, Chemistry, Pharmacology and Clinical Uses. Dekker, New York, 1975. 

Treatment of cells with vinblastine or vincristine can result in the formation of paracrystals, complexes containing the alkaloid molecules and tubulin dimers in a 1 1 ratio. Paracrystal formation in neuronal tissue of a freshwater snail has been proposed as a model for the neurotoxic effects of Catharanthus alkaloids and derivatives 44). Vincristine is approximately 10-fold more active than vinblastine as an inducer of paracrystal formation when snail neuronal tissue is treated with high concentrations (150 lM) of the alkaloids. 

The mechanism of action of Catharanthus alkaloids involves entry into the cell, binding to tubulin, and interference with cellular metabolic functions. The predominant observed effect is often mitotic arrest, but other effects on cellular organization and movement can also be demonstrated. It is not unequivocally clear that the mitotic effect is, in vivo, of greater importance than other tubulin-mediated effects (33). 

The mechanism of action of Catharanthus alkaloids undoubtedly relates to their effect on tubulin aggregation and consequent microtubule assembly and function. As microtubular function is intracellular, the alkaloids have to enter cells and remain within them to be effective. 

The preceding discussion is obviously incomplete. Furthermore, chemotherapeutic and other indications for the use of Catharanthus alkaloids are always changing. Nonetheless, it seems apparent that their inclusion in therapeutic regimens is, at least in part, responsible for the success of these regimens in both malignant and nonmalignant disease. It is hoped that, through chemical modification, their effectiveness will only increase. 

In these cases the formal //-ammo acid relationship often is a result of late stage condensation or cyclization reactions (e.g. Mannich-type, Pictet-Spengler) within the biosynthesis Typical examples are cocaine and correlated tropane alkaloids, Catharanthus alkaloids or Iboga alkaloids like heyneanine. 

The association of cytochrome P450s with organelles other than the ER may have important implications for the biosynthesis of alkaloids. It may help to explain why biochemical localization studies have shown that certain reactions in a pathway occur within the chloroplast. In the case of Catharanthus alkaloids, the 3 rd to last step in vindoline biosynthesis involves a chloroplast thylakoid associated N-methyltransferase.22 The arguments for participation of chloroplasts in this reaction include the possibility that the previous step involving hydration of the 2,3 double bond might require a chloroplast based oxidation reaction (Fig 8.6). The conclusive identification of specific cytochrome P4S0 enzymes in chloroplasts suggests that this hypothesis should be tested. 

Van der Heijden R, Jacobs DI, Snoeijer W, Mallard DVR. The Catharanthus alkaloids pharmacognosy and biotechnology. Curr. 

Figure 1 Structures of natural and synthetic Catharanthus alkaloids.

Higher plants have yielded many effective, clinically useful anticancer drugs, including those derived from Catharanthus alkaloids, Taxus diterpenes, Camptotheca alkaloids, and Podophyllum lignans. Research in this area has been reviewed extensively (3-13). 

Catharanthus alkaloids, particularly vinblastine (Al) and vincristine (A2), are well known anticancer drugs, which are used clinically to treat Hodgkin s lymphoma and acute childhood lymphoblastic leukemia, respectively. These alkaloids interact with tubulin, a protein necessary for cell division, and are inhibitors of mitosis (the process of cell division). 

Barnett CJ, Cullinan GJ, Gerzon K, Hoying RC, Jones WE, Newlon WM, Poore GA, Robison RL, Sweeney MJ, et al. Structure-activity relationships of dimeric Catharanthus alkaloids. 1. Deacetyl vinblastine amide vindesine sulfate. J. Med. Chem. 1978 21 88-96. 

K.Gerzon, "Dimeric Catharanthus Alkaloids," in J. M. Cassady and J. D. Douros, Eds., Anticancer Agents Based on Natural Product Models, Academic Press, New York, 1980, pp. 271-317. 

I = 21 y = 0.394 r = 0.9476 F = 49.8 where log P is the hydrophobicity, bondrefr is the molecular refractivity, delta is the submolecular polarity parameter, ind indicator variable (0 for heterocyclics and 1 for benzene derivatives). Calculations indicated that PBD-coated alumina behaves as an RP stationary phase, the bulkiness and the polarity of the solute significantly influencing the retention. The separation efficiency of PBD-coated alumina was compared with those of other stationary phases for the analysis of Catharanthus alkaloids. It was established that the pH of the mobile phase, the concentration and type of the organic modifier, and the presence of salt simultaneously influence the retention. In this special case, the efficiency of PBD-coated alumina was inferior to that of ODS. The retention characteristics of polyethylene-coated alumina (PE-Alu) have been studied in detail using various nonionic surfactants as model compounds.It was found that PE-Alu behaves as an RP stationary phase and separates the surfactants according to the character of the hydrophobic moiety. The relationship between the physicochemical descriptors of 25 aromatic solutes and their retention on PE-coated silica (PE-Si) and PE-Alu was elucidated by stepwise regression analysis. 

RETENTION DATA FOR SOME CATHARANTHUS ALKALOIDS AND SEMISYNTHETIC DERIVATIVES (Fig.8.2)26 ... 

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