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

• Five metabolites of contraceptive drug etonogestrel (1) were synthesized through biotransformation by fungi.
• Biotransformation of 1Cunninghamella blakesleeana yielded metabolites 2–6.
• Biotransformation of 1Cunninghamella echinulata yielded metabolites 2, 4, and 6.
• 6β-Hydroxy-etonogestrel (5) was found to be active against β-glucuronidase enzyme.

Biotransformation of a steroidal contraceptive drug, etonogestrel (1), (13-ethyl-17β-hydroxy-11-methylene-18,19-dinor-17α-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 6β-hydroxy-11,22-epoxy-etonogestrel (2), 11,22-epoxy-etonogestrel (3), 10β-hydroxy-etonogestrel (4), 6β-hydroxy-etonogestrel (5), and 14α-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 IC50 value of 13.97 ± 0.12 μM, in comparison to standard compound, d-saccharic acid 1,4-lactone (IC50 = 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.

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