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.
Highlights
The clinical usefulness of antimitotic compounds that interfere with microtubule dynamics via the colchicine binding site, including 2-methoxyestradiol (2ME), chalcones and combretastatins, are currently under investigation [1]
Kinetics data (C) demonstrates that ESE-15-ol has an almost 2-fold higher affinity for the carbonic anhydrase IX (CAIX) mimic when compared to the wild-type carbonic anhydrase II (CAII). a Experimental inhibition constants were determined by Sippel et al (2011) [35]. b The inhibition of the catalyzed exchange of 18O between CO2 and water as measured by membrane-inlet mass spectrometry was used to determine the experimental inhibition constants (Ki) of ESE-15-ol [16]
Kinetics data indicated that ESE-15-ol has an almost 2-fold higher affinity for the CAIX mimic when compared to the wild-type CAII (Figures 1B and 2)
Summary
The clinical usefulness of antimitotic compounds that interfere with microtubule dynamics via the colchicine binding site, including 2-methoxyestradiol (2ME), chalcones and combretastatins, are currently under investigation [1]. Mediocre biopharmaceutical properties such as short half-life and low bioavailability of 2ME have prompted the research and development of estradiol analogues with improved in vivo efficacy [2,3,4,5,6]. The sulfamate group allows the compounds to bind the carbonic anhydrase II (CAII) of red blood cells in a reversible manner [10] This allows the bypass of first pass metabolism due to the slow release into the blood stream from CAII, resulting in increased bioavaliability [7,9]. The in vitro effects of ESE-15-ol on cell growth, morphology, cell cycling and mitochondrial membrane potential in three different breast cell lines, including the metastatic MDA-MB-231, tumorigenic MCF-7 (estrogen receptor positive) and non-tumorigenic
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