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

• Published in: Bioorganic chemistry 2024-12, Vol.154, p.108025, Article 108025
• Main Authors: Aamer, Muhammad, Atif, Muhammad, Siddiqui, Mahwish, Zafar, Humaira, Irshad, Rimsha, Atia-tul-Wahab, Khan, Farooq-Ahmad, Liang, Dong, Iqbal Choudhary, M., Wang, Yan
• Format: Article
• Language: English
• Subjects: 11β-Hydroxy-dianabol; Aromatase inhibition; Biocatalytic transformation; Cunninghamella blakesleeana; ER+ breast cancer; Gibberella fujikuroi
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.108025

[Display omitted] •11β-Hydroxy-dianabol was transformed by fungi for the first time.•Five new metabolites were successfully obtained.•Metabolites of 11β-hydroxy-dianabol were found to be potent aromatase inhibitors.•All metabolites were non-cytotoxic to normal cell line.•An in silico approach was applied to explore protein–ligand interactions. 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 IC50 values in the range of 2.01–3.13 μM as compared to the standard drug, exemestane (IC50 = 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.