In vitro evaluation of ESE-15-ol, an Estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity

Show simple item record Stander, Barend Andre Joubert, Fourie Tu, Chingkuang Sippel, Katherine H. McKenna, Robert Joubert, Annie M.
dc.contributor.editor Ahmad, Aamir 2013-02-05T11:35:58Z 2013-02-05T11:35:58Z 2012-12
dc.description.abstract Antimitotic compounds are still one of the most widely used chemotherapeutic anticancer drugs in the clinic today. Given their effectiveness against cancer it is beneficial to continue enhancing these drugs. One way is to improve the bioavailability and efficacy by synthesizing derivatives that reversibly bind to carbonic anhydrase II (CAII) in red blood cells followed by a slow release into the blood circulation system. In the present study we describe the in vitro biological activity of a reduced derivative of 2-ethyl-3-O-sulphamoyl-estradiol (2EE), 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol (ESE-15-ol). ESE-15-ol is capable of inhibiting carbonic anhydrase activity in the nanomolar range and is selective towards a mimic of carbonic anhydrase IX when compared to the CAII isoform. Docking studies using Autodock Vina suggest that the dehydration of the D-ring plays a role towards the selectivity of ESE-15-ol to CAIX and that the binding mode of ESE-15-ol is substantially different when compared to 2EE. ESE-15-ol is able to reduce cell growth to 50% after 48 h at 50–75 nM in MCF- 7, MDA-MB-231, and MCF-12A cells. The compound is the least potent against the non-tumorigenic MCF-12A cells. In vitro mechanistic studies demonstrate that the newly synthesized compound induces mitochondrial membrane depolarization, abrogates the phosphorylation status of Bcl-2 and affects gene expression of genes associated with cell death and mitosis. en_US
dc.description.librarian am2013 en_US
dc.description.librarian ay2013 en
dc.description.sponsorship Grants from the Medical Research Council of South Africa (AG374, AK076), the Cancer Association of South Africa (AK246), National Research Foundation (NRF) (AL239), the Research Committee of the Faculty of Health Sciences (RESCOM) of University of Pretoria, and the Struwig-Germeshuysen Cancer Research Trust of South Africa (AJ038, AN074). en_US
dc.description.uri en_US
dc.identifier.citation Stander BA, Joubert F, Tu C, Sippel KH, McKenna R, et al. (2012) In Vitro Evaluation of ESE-15-ol, an Estradiol Analogue with Nanomolar Antimitotic and Carbonic Anhydrase Inhibitory Activity. PLoS ONE 7(12): e52205. doi:10.1371/journal.pone.0052205 en_US
dc.identifier.issn 1932-6203
dc.identifier.other 10.1371/journal.pone.0052205
dc.language.iso en en_US
dc.publisher Public Library of Science en_US
dc.rights © 2012 Stander et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use en_US
dc.subject Antimitotic compounds en_US
dc.subject Chemotherapeutic anticancer drugs en_US
dc.subject.lcsh Cancer -- Treatment en
dc.title In vitro evaluation of ESE-15-ol, an Estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity en_US
dc.type Article en_US

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