Selective antitumour activity and ERα molecular docking studies of newly synthesizedd-homo fused steroidal tetrazoles

Here we report a convenient “click” synthesis for D-homo fused steroidal tetrazoles 11–14 from androstane and estratriene 16,17-seco-16-nitrile-17-mesyloxy derivatives 5–8, via intramolecular 1,3-dipolar cycloaddition from in situ generated 16,17-seco-17-azido-16-nitriles 5a–8a. Products were validated by 1H/13C-NMR, IR, HRMS, and structurally characterized by X-ray crystallography and computational methods. Compounds were evaluated as potential anti-proliferative agents against a panel of human cancer cell lines. D-Homo fused steroidal tetrazoles 13 and 14 appear to have specific, selective anti-proliferative effects against estrogen receptor positive (ER+) breast adenocarcinoma cells, which correlate with binding energies calculated from molecular docking to the estrogen receptor α-ligand binding domain (ERα-LBD). Moreover, molecular docking suggests that D-ring fused steroidal tetrazoles 13 and 14 could bind to ERα-LBD in a manner similar to known anti-estrogenic compounds. Addition of a D-homo fused tetrazole group appears to structurally mimic the hydrogen bonding potential of β-estradiol, suggesting their general utility in designing novel steroidal tetrazole derivatives as anti-estrogens or inhibitors of steroidogenic enzymes.