This investigation is continuing despite an elegant total synthesis of (-)-N(8)-norphysostigmine just published by Japanese scientists.71
ConclusionAnalogues of colchicine (ethyl carbamate) and thiocolchicine (3-demethylthiocolchicine) which show interesting biological properties have to await further pharmacological and toxicological evaluation to establish their potential clinical usefulness.The finding, that natural colchicinoids and derived alio congeners bind to tubulin as aS-configurated biaryls, will greatly help in further study of elucidating the mechanism by which they bind to the colchicine binding site on the protein. Systematic efforts to structurally modify compounds of the alio series paid off, since it clearly showed that the methoxy groups at C(l), C(2), and C(9) are required for the binding to tubulin and shifting the acetamido group from C(7) to C(5) afforded an inactive compound.With efficient synthesis of Calabar alkaloids leading to both optical isomers on hand, it now is up to medicinal chemists to make further molecular changes, which (71) Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109. hopefully may lead to clinically useful analgesics and cholinergic agents. Further pharmacological evaluation of (+)-physostigmine and of (-)-Ml)-norphysostigmine, which emerged as interesting compounds, is indicated. In both series of alkaloids discussed, the colchicines and the physostigmines, optical resolution of racemic mixtures and testing optically active isomers instead of racemic mixtures, was pivotal for obtaining useful information.Acknowledgment. The research presented here could not have been accomplished without the input made by many devoted and hard working scientists. This, in the case of colchicine, included the following Ph.D's: H.
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