Microbial transformation of contraceptive drug etonogestrel into new metabolites with Cunninghamella blakesleeana and Cunninghamella echinulata

摘要

Biotransformation of a steroidal contraceptive drug, etonogestrel (1), (13-ethyl-17 beta-hydroxy-11-methylene-18,19-dinor-17 alpha-pregn-4-en-20-yn-3-one) was investigated with Cunninghamella blakesleeana and C. echinulata. Five metabolites 2-6 were obtained on incubation of 1 with Cunninghamella blakesleeana, and three metabolites, 2, 4, and 6 were isolated from the transformation of 1 with C echinulata. Among them, metabolites 2-4 were identified as new compounds. Their structures were deduced as 6 beta-hydroxy-11,22-epoxy-etonogestrel (2), 11,22-epoxy-etonogestrel (3), 10 beta-hydroxy-etonogestrel (4), 6 beta-hydroxy-etonogestrel (5), and 14 alpha-hydroxy-etonogestrel (6). Compounds 1-6 were evaluated for various biological activities. Interestingly, compound 5 was found to be active against beta-glucuronidase enzyme with IC50 value of 13.97 +/- 0.12 mu M, in comparison to standard compound, D-saccharic acid 1,4-lactone (IC50 = 45.75 +/- 2.16 mu M). Intestinal bacteria produce beta-glucuronidase. Increased activity of beta-glucuronidase is responsible for the hydrolyses of glucuronic acid conjugates of estrogen and other toxic substances in the colon, which plays a key role in the etiology of colon cancer. Inhibition of beta-glucoronidase enzyme therefore has a therapeutic significance. Compounds 1-6 were also found to be non cytotoxic against 3T3 mouse fibroblast cell lines. (C) 2016 Published by Elsevier Inc.