Stander B.A., Joubert F., Tu C., Sippel K.H., McKenna R., Joubert A.M.
Department of Physiology, University of Pretoria, Pretoria, Gauteng, South Africa; Department of Biochemistry, Bioinformatics and Computational Biology Unit, University of Pretoria, Pretoria, Gauteng, South Africa; Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, United States; Baylor College of Medicine, Houston, TX, United States; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, United States
Stander, B.A., Department of Physiology, University of Pretoria, Pretoria, Gauteng, South Africa; Joubert, F., Department of Biochemistry, Bioinformatics and Computational Biology Unit, University of Pretoria, Pretoria, Gauteng, South Africa; Tu, C., Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, United States; Sippel, K.H., Baylor College of Medicine, Houston, TX, United States; McKenna, R., Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, United States; Joubert, A.M., Department of Physiology, University of Pretoria, Pretoria, Gauteng, South Africa
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. © 2012 Stander et al.
2 ethyl 3 o sulphamoyl estra 1,3,5(10),15 tetraen 17 ol; antineoplastic agent; carbonate dehydratase; carbonate dehydratase II; carbonate dehydratase IX; protein bcl 2; unclassified drug; antineoplastic activity; antiproliferative activity; apoptosis; article; binding affinity; cancer inhibition; controlled study; drug structure; enzyme activity; enzyme inhibition; enzyme mechanism; gene expression; genetic association; in vitro study; inhibition kinetics; membrane depolarization; mitochondrial membrane potential; molecular docking; molecular model; protein phosphorylation; tumor cell destruction; Antimitotic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Cycle; Cell Proliferation; Estradiol; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial; Molecular Docking Simulation; Neoplasm Metastasis; Phosphorylation; Protein Conformation; Proto-Oncogene Proteins c-bcl-2; Serine; Sulfonamides; Tubulin