Leucophyl · Total Synthesis of Leucophyllidine

Total Synthesis of Leucophyllidine

The search for potent chemotherapeutic agents with anticancer activity and issued from natural sources is still attracting a wide interest as drug-resistance tends to proliferate. Terpene indole alkaloids constitute a family of more than 3000 members, in which only a few exhibit physiological effects on mammals. Vincristine and vinblastine, isolated from Catharanthus roseus, are the most well known, the former being used in the treatment of leukemia, while the latter was found active against Hodgkin’s disease. However, these alkaloids are rather expensive. For instance, 1 kg of vinblastine costs around a million dollars and the annual production in the world is 12 kg. It is interesting noticing that while vinca alkaloids are still the subject of numerous studies, there is not a similar interest for analogues. However, new biologically relevant dimeric alkaloids continue to be discovered that might be worth considering for future clinical applications. This is the case for Leucophyllidine, recently isolated from the stem-bark of Leuconotis griffithii, woody climbers found in Indonesia and Peninsular Malaysia. This alkaloid exhibits a promising in vitro cytotoxicity toward vincristine-resistant human KB cells with IC50 of less than 3 ug/mol. While the level of activity is not outstanding, the selectivity toward resistant cells is of considerable interest in the quest for more efficient and targetable antitumor agents. Leucophyllidine is thus a promising target, and possesses an unusual quinoline sub-structure that opens new perspectives for the discovery of potent drugs in cancer chemotherapy. Kam and co-workers who isolated Leucophyllidine suggested that this alkaloid could have arisen from biomimetic coupling between two natural products Eburnamine and Eucophylline. These different elements stimulated our interest for leucophyllidine, leading to the present research project. The objective of the research program was thus three-fold, including : - the development of the first asymmetric total synthesis of Eucophylline and Leucophyllidine, - the design of new metal-free radical based methodologies using cyclopropenes, - the identification of a possible biogenetic pathway for the synthesis of Leucophyllidine in the plant. - and finally, in the endeavor of searching for more potent antitumor agents, the development of further biological testing of the final products and their intermediates.

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