Biotransformation and molecular docking studies of aromatase inhibitors

Abstract

Bioconversion of the aromatase inhibitor formestane (4-hydroxyandrost-4-ene-3,17-dione) (1) by the fungus Rhizopus oryzae ATCC 11145 resulted in a new minor metabolite 3,5α-dihydroxyandrost-2-ene-4,17-dione (2) and the known 4β,5α-dihydroxyandrostane-4,17-dione (3) as the major product. The structural elucidation and bioactivities of these metabolites are reported herein. Molecular modeling studies of the interactions between these metabolites and the aromatase protein indicated that acidic (D309), basic (R115), polar (T310), aromatic (F134, F221, and W224), and non-polar (I133, I305, A306, V369, V370, L372, V373, M374, and L477) amino acid residues contribute important interactions with the steroidal substrates. These combined experimental and theoretical studies provide fresh insights for the further development of more potent aromatase inhibitors.

Targeting Overexpressed Aromatase in Estrogen Positive Human Cancers: Isorottlerin Emerged as Potential Inhibitor of Aromatase in Computational Docking and Dynamics Simulation Study

“…At present, third generation non-steroidal aromatase inhibitors like anastrozole and letrozole are utilized in the treatment of post-menopausal breast and ovarian cancers [10]. In addition, the steroid, exemenstane is used to irreversibly bind to the aromatase enzyme and thereby inhibiting the enzyme activity [11]. Nonetheless, the side effects of non-steroidal drugs, anastrozole and letrozole include joint and muscle pain, menopausal symptoms, depression, sleeplessness, osteoporosis, high cholesterol, carpal tunnel syndrome, blood clots and fatigue [12,13].…”

Biotransformation of Steroids Using Different Microorganisms

“…4-Hydroxyandrost-4-ene-3,17-dione (formestane, 216) is an irreversible aromatase inhibitor and therapeutically used in breast cancer treatment in postmenopausal women. Bioconversion of 216 using Rhizopus oryzae (ATCC 1145) resulted in the production of 4β,5α-dihydroxyandrost-3,17-dione (217, 8.6%) and 3,5α-dihydroxyandrost-2-ene-4,17-dione (218)[98], while the biotransformation of 217 using Beauveria bassiana produced 4,17β-dihydroxyandrost-4-en-3-one (219, 5.3%), 3α,17β-dihydroxy-5β-androstan-4-one (220, 0.9%), and 4,11α,17βtrihydroxyandrost-4-en-3-one (221, 2.4%) (Figure 29)[99].Methyltestosterone (222), an anabolic steroid, was transformed by Mucor racemosus in 5 days to produce two monohydroxylated…”