In vitro evaluation of ESE-15-ol, an Estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity
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Date
Authors
Stander, Barend Andre
Joubert, Fourie
Tu, Chingkuang
Sippel, Katherine H.
McKenna, Robert
Joubert, Annie M.
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
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.
Description
Keywords
Antimitotic compounds, Chemotherapeutic anticancer drugs
Sustainable Development Goals
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