Microbial catalyzed derivatization of canrenone with Glomerella fusarioides, and Cunninghamella blakesleeana, and evaluation of aromatase inhibitory activity of the resulting metabolites.

The purpose of this study was to identify potential aromatase inhibitors, which might play a role in preventing breast cancer. The fungal-catalyzed microbial transformation of an anti-mineralocorticoid, canrenone (1), was catalyzed by Glomerella fusarioides, and Cunninghamella blakesleeana. Bioconversion of canrenone (1) with G. fusarioides provided a new polar metabolite 2, and two known metabolites 3 and 4, while C. blakesleana transformed compound 1 into two known polar metabolites 4, and 5. Modern spectroscopic techniques were employed to identify the structures of metabolites as 1-dehydro-11α-hydroxycanrenone (2), 1-dehydrocanrenone (3), 11α-hydroxycanrenone (4), and 11β-hydroxycanrenone (5). The SingleCrystal X-ray Diffraction (SCXRD) based structures of metabolites 2, and 3 are reported here for the first time. Canrenone (1) and the resulting metabolites 2-4 were evaluated for their human aromatase inhibitory activity. Compounds 1-4 showed the IC values of 0.288 ± 0.0392, 0.372 ± 0.002, 0.328 ± 0.0083, and 1.102 ± 0.099, µM comparable to the standard drug, exemestane (0.26 ± 0.011 µM). All transformed products were found non-cytotoxic to human fibroblast (BJ) cell line. Furthermore, the docking studies predicted the interaction of potential inhibitors with the active site residues of the enzyme via hydrogen bonding and other non-covalent interactions. Simulation studies predicted the formation of stable enzyme-inhibitor complexes with no or insignificant perturbation during the simulation time of 100 nsec. Hence, these inhibitors may serve as preliminary hits for drug discovery against ER+ breast cancer.