A novel thiadiazole-steroid hybrid as a CYP19A1 inhibitor: Synthesis, molecular interaction analysis and assessment of steroid receptor signaling.

The enzyme aromatase (CYP19A1) is an important target for the discovery of new therapeutic drugs against breast cancer. A series of novel heteroaryl steroidal derivatives, C-2- and C-16-thiadiazole-substituted estranes, were synthesized and biologically evaluated as potential aromatase inhibitors. These compounds exhibited cytotoxicity against breast cancer cells with IC50 values of 5.5 µM and higher. The lead compound, 2-(2'-P(O)(NHtBu)2-1',3',4'-thiadiazole)-Δ1,3,5(10)-estratrien-17-one, was shown to be selective against MCF7 cells with IC50 (MCF7) = 5.5 µM vs IC50 (MDA-MB-231) = 26.1 µM. It acts as both a potent selective agent blocking CYP19A1 and an effective apoptosis inducer, with no effects on the hormone receptors ERα and AR. The toxicity of the lead compound against normal epithelial cells has not been revealed. Molecular docking was used to more accurately define the binding mode of the lead compound to CYP19A1. In a word, here we describe a novel heteroaryl steroidal derivative promising as a CYP19A1 inhibitor for the treatment of hormone-dependent breast cancer.