Structural modifications of the vinca alkaloids

Abstract

The vinca alkaloids were discovered independently in two separate laboratories by a combinat ion of serendipity and what we have called rational broad spectrum tumor screening. In the first case, R. L. Noble and his colleagues in the Collip Labora tory at the University of Western Ontar io were examining extracts ofCatharanthus roseus G. Don ( Vinca rosea Linn.) for their effects on blood glucose because of unconfirmed reports in various parts of the world that the plant was being used for the treatment of diabetes. These investigators (4) found by chance observation that the extracts produced profound leukopenia in the rat, and they isolated an alkaloid which demonstrated such activity as a crystalline sulfate, which they named vincaleukoblastine (VLB). They speculated that it might have potential chemotherapeutic properties. This is the drug which is currently marketed as Velban ~'~ (vinblastine sulfate, Lilly). Unknown to the Canadian group, a group of investigators in the Lilly Research Laboratories had observed profound activity in extracts from the same plant against the P-1534 lymphocytic leukemia in DBA/2 mice and had isolated a second alkaloid with antileukemic activity which they named leurosine (3). We were also able to show that after VLB and leurosine were removed from the extracts that there were components remaining with profound ant i tumor activity. These were eventually identified as leurocristine (Oncovin, vincristine sulphate, Lilly) and leurosidine (12). The discovery in the Lilly Research Laboratories resulted from a privately funded ant i tumor screening program mounted in response to a national effort to increase the detection and development of new anticancer drugs through what was then the Cancer Chemotherapy National Service Center (CCNSC). We had long felt that harnessing the major pharmaceutical laboratories to a single set of tests or test systems would have been an error. It had been the experience of most such laboratories that, as new systems, tests, techniques, etc., are devised, a new class of agent was frequently found. The more varied the system in use, the greater the probability of different kinds of materials being detected. In the nationally organized program, the screening philosophy appeared to be based upon the concept of using as few detection systems as possible that would detect the largest number of drugs currently considered as having clinical activity. This was clearly an at tempt at a cost-effective approach. Our concern was that cancer was a heterogenous family of proliferative diseases, and that just as cancer drugs had tumor spectra, experimental neoplasms also had drug spectra. I f this were true, continuous use of a few or even single murine neoplasms for cancer screening might not be expected to detect new or novel drugs, much less predict for activity against a broad spectrum of neoplasms and histological types. While performing well in terms of detecting novel structures, our system did not predict