Vinblastine analog synthesis

Cabot, M. C., Giulano, A. E., Han, T-Y., and Liu, Y-Y., 1999, SDZ PSC 833, the cyclosporin A analog and multidrug resistance modulator, activates ceramide synthesis and increases vinblastine sensitivity in drug-sensitive and drag-resistant cancer cells. Cancer Res. 59 880-885. 

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. 

Synthesis and SAR of novel ll -vinorelbine, 12 -vinblastine, and 12 -vincristine alkaloid analogs... 

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