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Issue 2, 2013
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Selective antitumour activity and ERα molecular docking studies of newly synthesized d-homo fused steroidal tetrazoles

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Abstract

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.

Graphical abstract: Selective antitumour activity and ERα molecular docking studies of newly synthesized d-homo fused steroidal tetrazoles

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Supplementary files

Article information


Submitted
21 Sep 2012
Accepted
02 Nov 2012
First published
06 Nov 2012

Med. Chem. Commun., 2013,4, 317-323
Article type
Concise Article

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

K. M. Penov-Gaši, A. M. Oklješa, E. T. Petri, A. S. Ćelić, E. A. Djurendić, O. R. Klisurić, J. J. Csanadi, G. Batta, A. R. Nikolić, D. S. Jakimov and M. N. Sakač, Med. Chem. Commun., 2013, 4, 317
DOI: 10.1039/C2MD20327H

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