title: In vitro evaluation of ESE-15-ol, an estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity.
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.
authors.affiliation: Department of Physiology, University of Pretoria, Pretoria, Gauteng, South Africa. standerandre@gmail.com
authors.forename: Barend Andre
authors.initials: BA
authors.lastname: Stander
authors.forename: Fourie
authors.initials: F
authors.lastname: Joubert
authors.forename: Chingkuang
authors.initials: C
authors.lastname: Tu
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Sippel
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Annie Margaretha
authors.initials: AM
authors.lastname: Joubert
mesh_terms: D050256:Antimitotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
chemical_list: C581967:2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-17-ol; D050256:Antimitotic Agents; D002257:Carbonic Anhydrase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D014404:Tubulin; D012694:Serine; D004958:Estradiol; D002256:Carbonic Anhydrases