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

Abstract Biotransformation of a steroidal contraceptive drug, etonogestrel ( 1 ), (13-ethyl-17 β -hydroxy-11-methylene-18,19-dinor-17 α -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 β -hydroxy-11,22-epoxy-etonogestrel ( 2 ), 11,22-epoxy-etonogestrel ( 3 ), 10 β -hydroxy-etonogestrel ( 4 ), 6 β -hydroxy-etonogestrel ( 5 ), and 14 α -hydroxy-etonogestrel ( 6 ). Compounds 1–6 were evaluated for various biological activities. Interestingly, compound 5 was found to be active against β -glucuronidase enzyme with IC 50 value of 13.97 ± 0.12 μM, in comparison to standard compound, d -saccharic acid 1,4-lactone (IC 50  = 45.75 ± 2.16 μM). Intestinal bacteria produce β -glucuronidase. Increased activity of β -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 β -glucoronidase enzyme therefore has a therapeutic significance. Compounds 1–6 were also found to be non cytotoxic against 3T3 mouse fibroblast cell lines.