Potent aromatase inhibitors through fungal transformation of anti-cancer drug testolactone: An approach towards treatment of breast cancer

摘要

Biotransformation of an aromatase inhibitor, testolactone (1), yielded five new metabolites, 7α-hydroxy-3-oxo-13,17-secoandrosta-1,4-dieno-17,13α-lactone (2), 7β-hydroxy-3-oxo-13,17-seco-5β-androsta-1-eno-17,13α-lactone (3), 3α,11β-dihydroxy-13,17-seco-5β-androsta-17,13α-lactone (4), 4β,5β-epoxy-3β-hydroxy-13,17-secoandrosta-1-eno-17,13α-lactone (5), and 4β,5β-epoxy-3α-hydroxy-13,17-secoandrosta-1-eno-17,13α-lactone (6). Aromatase (estrogen synthase) involves in the synthesis of estrogen, and promotes the growth of breast cancerous cells. It is a key target for the discovery of chemotherapeutic agents against ER+ (estrogen-positive) breast-cancers and several other diseases caused by overexpression of aromatase enzyme. Metabolites 3 (IC₅₀=8.60±0.402 nM), and 4 (IC₅₀=9.23±1.31 nM) were identified as potent inhibitors against human aromatase enzyme, in comparison to 1 (IC₅₀=0.716±0.031 μM), and the standard aromatase inhibiting drug, exemestane (IC₅₀=0.232±0.031 μM). Derivatives 2 (IC₅₀=11.68±0.73 μM), 5 (IC₅₀=10.37±0.50 μM) and 6 (IC₅₀=0.82±0.059 μM) have also a good inhibition against aromatase enzyme. Therefore, metabolites 2-6 have the potential to serve as therapeutic agents against diseases caused by aromatase enzyme, including breast cancer.