Further transformation of fungal catalyzed transformed metabolite 11β-hydroxy-dianabol into new aromatase inhibitors.

Secondary biotransformation of 11β-hydroxy-dianabol (11β,17β-dihydroxy-17α-methylandrost-1,4-dien-3-one) (1), catalyzed by using two fungi Gibberella fujikuroi and Cunninghamella blakesleeana at ambient conditions, was carried out to synthesize its analogues. Transformation of compound 1 with G. fujikuroi yielded a new metabolite, 11β, 17β-dihydroxy-17α-methyl-5β-androst-1-ene-3-one (2), while four new derivatives, 6β, 17β-dihydroxy-17α-methylandrost-1,4-diene-3,11-dione (3), 15α,17β-dihydroxy-17α-methylandrost-1,4-diene-3,11-dione (4), 6β,11β,17β-trihydroxy-17α-methylandrost-1,4-dien-3-one (5), and 7β,11β,17β-trihydroxy-17α-methylandrost-1,4-dien-3-one (6) were obtained by transformation with C. blakesleeana. Compounds 1-6 showed a significant aromatase inhibition with IC values in the range of 2.01-3.13 μM as compared to the standard drug, exemestane (IC = 0.21 ± 0.16 μM). Aromatase is a valid target for drug discovery against ER+ breast cancers. Compounds 1-6 were subjected to molecular docking studies to predict the key interactions, and the MMGBSA studies to analyze the binding affinity and thermal stability of the protein-ligand complexes. Further, the relationship between the metabolites 1-6 and breast tumor androgen receptors was evaluated by in silico approach to analyze the binding interactions between androgen receptors and metabolites. Moreover, compounds 1-6 were found as non-cytotoxic to BJ (Human fibroblast) normal cell line. Hence, these molecules can be further studied for optimization as potential aromatase inhibitors against breast cancer.