Synthesis and Cytotoxicity of О- and N-Acyl Derivatives of Azepanobetulin

Abstract

A five-stage synthesis of azepanobetulin from betulin with a total yield of 47% has been carried out. The acylation of azepanobetulin with anhydrides or acid chlorides (acetic, phthalic, nicotinic) and tosylation resulted in the synthesis of О- and N-derivatives of azepanobetulin. Azepanobetulin, its 28-tosylate, 3а-N,28-О-dinicotinoate, and 3-N,28-О-diacetate showed antitumor activity toward a large panel of cancer cells, whereas mono-С28-acylates were ineffective. In contrast to azepanobetulin, its azepanone analog did not possess cytotoxicity. Leukemia and colon tumor cells were most sensitive to azepanobetulin and its bisacylates. Azepanobetulin was highly effective toward the melanoma cell line. 28-О-para-Tosylazepanobetulin exhibited antitumor activity toward nine cancer types and produced a cytocidal effect toward 31 cell lines.