Search for New Tumor Promoters Employing Chemical Calculation

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The purpose of this research project are discovery of common structural informations of TPA-type tumor promoters having different skeletal structures (phorbol esters and teleocidins) by organic synthesis and chemical calculation, and discovery of new biologically active compounds. Teleocidins are known to exist an equilibrium between at least two conformational states in solution, the twist and sofa forms. The low energy barrier between the two conformers makes it difficult to identify the mode of interaction of these promoters with common targets. Benzolactam-Vs, in which the indole ring of teleocidins was replaced with a benzene ring, were sesigned in attempt to reproduce the active conformation of teleocidins and synthsized. The 8-membered lactam (BL-V8-310) exist only in the twist form in solution and 9-membered lactam (BL-V9-310) exist only in the sofa form. The strong activities of BL-V8-310 and the lack of activity of BL-V9-310 clearly indicated that the active conformation for tumor-promoting activity of teleocidins is close to the twist form. We also designed several oxygenated steroids in which functional groups including are arranged analogously to those of phorbol esters. One of the oxygenated steroids was found to be a specific ligand for Cytosolic Nuclear Tumor Promoter Binding Protein.