Biotransformation of metenolone acetate and epiandrosterone by fungi and evaluation of resulting metabolites for aromatase inhibition

• Published in: Steroids 2024-02, Vol.202, p.109345-109345, Article 109345
• Main Authors: Abdul Karim, Aerab, Atia-Tul-Wahab, Aziz, Ambreen, Shaikh, Nimra Naveed, Choudhary, M Iqbal
• Format: Article
• Language: English
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2023.109345

The present study describes the microbial transformation of anabolic drugs, metenolone acetate (1), and epiandrosterone (6). Three new metabolites, 6β,17β-dihydroxy-1-methyl-3-oxo-5α-androst-1-en (2), 5α,15α-dihydroxy-1-methyl-3-oxo-1-en-17-yl acetate (3), 15β-hydroxy-1-methyl-3-oxo-5α-androst-1,4-dien-17-yl acetate (4), and a known metabolite, 17β-hydroxy-1-methyl-4-androstadiene-3-one (5) were obtained by biotransformation of metenolone acetate (1) via Trametes hirsuta mushroom. Metabolites 7, and 8 were obtained from the incubation of epiandrosterone (6) with Cunninghamella blakesleeana. While bioconversion of compound 6 with Aspergillus alliaceus yielded seven known metabolites 9-15. Modern spectroscopic techniques were employed for the structure elucidation of biotransformed products. All compounds were evaluated for their aromatase inhibitory activity. Among them, new metabolite 3 exhibited a significant human placental aromatase activity with an IC  = 19.602 ± 0.47 µM, as compared to standard anti-cancer drug exemestane (IC  = 0.232 ± 0.031 µM), whereas, metabolite 5 (IC 0.0049 ± 0.0032 µM) exhibited a very potent activity. While substrate 6, and metabolites 2, 7, and 9 were found inactive. Aromatase plays a key role in the biosynthesis of estrogen hormone, responsible for cancer cell proliferation. Its inhibition is therefore targeted for the treatment of ER + breast cancer. Further structural modifications (lead optimization) of compound 3 can lead to more potent aromatase inhibition for possible treatment of ER + breast cancer.