Bisindole alkaloids pharmacology

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

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... 

PHARMACOLOGY OF ANTITUMOR BISINDOLE ALKALOIDS FROM CATHARANTHUS... 

Among the natural products that can be isolated from Voacanga species, it is the alkaloids which account for the wide range of pharmacological activies and thus medicinal uses. For instance, the bisindole alkaloid amataine isolated from Voacanga exhibited cytotoxicity effects in vitro and conld be nsed in chemotherapy as cytotoxic gronp 44). 

The first volume in this series was, perhaps, sui generis, in that it comprised reviews of developments in alkaloid chemistry over an eighteen-month period instead of the twelve-month period adopted for subsequent Reports. There was also included sufficient background material to enable the new work to be placed in perspective in its own particular area, as well as three summaries of a more extended kind these were concerned with the biosynthesis of the terpenoid indole alkaloids, the bisindole alkaloids, and alkaloids of current pharmacological or clinical interest. 

Tissue or cell cultures of Catharanthus roseus continue to be investigated, in the search for improved methods of production of pharmacologically important alkaloids. Three such investigations have recently been reported, and although several alkaloids were obtained, including some heteroyohimbine and yohimbine alkaloids, no new ones were encountered, and none of the valuable bisindole alkaloids was obtained. However, pleiocarpamine, one of the alkaloids isolated, had not previously been 6 2... 

Because of the important biological activities and unique chemical structures, monoterpenoid bisindole alkaloids have attracted considerable attention among researchers of natural product chemistry, synthetic organic chemistry, medicinal chemistry, plant science, pharmacology, and so on. Further studies on this class of alkaloids will certainly contribute to the great development of pure and applied science. 

McCormack, J. J., Pharmacology of antitumor bisindole alkaloids from Catharanthus, in The Alkaloids, Vol. 37 (A. Brossi and M. Suffness, eds.), 205-228, Academic Press, New York, 1990. 

McCormack, J.J. (1990) Pharmacology of Anti-tumor Bisindole Alkaloids from Catharanthus, Vol. 37. Academic Press, Inc., Orlando, FL, pp. 205-226. 

Brossi, A., Suffness, M. (Eds) (1990) Antitumor Bisindole Alkaloids from Catharanthus roseus (L.) Vol. 37, The Alkaloids Chemistry and Pharmacology, Vol. 37. 

---