Steroidal carbonitriles as potential aromatase inhibitors

Estrogens, responsible for the growth of hormone-dependant breast cancer are biosynthesized from androgens involving aromatase enzyme in the last rate limiting step. Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. Novel 4-phenylthia derivatives (2, 3 and 7) have been synthesized as aromatase inhibitors. The synthesized compounds (2, 3 and 7) exhibited noticeable enzyme inhibiting activity. Kinetics study of these compounds (2, 3, and 7) showed negligible inhibition of the enzyme under conditions conducive for irreversible inhibition of the enzyme. Introduction of unsaturation at C-4, C-1 & 4 or C-4 & 6 (compounds 5, 9 and 11) was observed to not be an effective strategy for entrancing aromatase inhibiting activity in 17-oxo-16β-carbonitrile derivatives. The d-seco derivatives (13–15 and 17) having unsaturation at C-4, C-1 & 4 or C-4 & 6 along with carbonitrile function in ring-D showed complete loss of aromatase inhibiting activity.

4-Phenylthia- and 4-(4-aminophenyl)thia-17β-hydroxy-4-androsten-3-one (2 and 3), and 16β-cyano-17β-hydroxy-4-phenylthia-4-androsten-3-one (7) were synthesized. One of the compounds (7) showed equal aromatase inhibitory potency to exemestane. However, it showed competitive inhibition of the enzyme unlike exemestane.Figure optionsDownload as PowerPoint slideHighlights
► 4-Phenylthia substituted (2, 3) and 16β-cyano (7) derivatives are synthesized.
► 4-Phenylthia-16β-cyano derivative (7) is equipotent to exemestane.
► Compounds having fractured androstane skeleton are totally devoid of activity.
► Kinetics study reveals that compound (7) is reversible inhibitor of the enzyme.