SYNTHESIS, CONFORMATION, AND BIOLOGICAL-ACTIVITY OF TELEOCIDIN MIMICS, BENZOLACTAMS - A CLARIFICATION OF THE CONFORMATIONAL FLEXIBILITY PROBLEM IN STRUCTURE-ACTIVITY STUDIES OF TELEOCIDINS

Tumor-promoter teleocidins and their active congeners (indolactams) ar e known to exist in an equilibrium between at least two conformational states in solution, the twist and sofa form, due to cis-trans isomeri zation of the amide bond and the steric effects of substituents on the nine-membered lactam ring. Benzolactam-Vs, in which the indole ring o f indolactams is replaced with a benzene ring, were designed and synth esized in an attempt to reproduce the active conformation of teleocidi ns. Among these benzolactams, eight-membered lactams (benzolactam-V8) can only exist in the twist form, and 9- and 10-membered lactams (benz olactam-V9 and -V10) exist exclusively in the sofa form in solution. T he stronger biological activity of benzolactam-V-8-310 than that of in dolactam-V (IL-V) and the inactivity of benzolactam-V-9-310 for differ entiation inducing activity of HL-60 clearly indicated that the twist form is close to the active conformation of teleocidins.