Department of Physiology, University of Pretoria, Pretoria, South Africa; Department of Biochemistry, Bioinformatics and Computational Biology Unit, University of Pretoria, Pretoria, South Africa
Stander, A., Department of Physiology, University of Pretoria, Pretoria, South Africa; Joubert, F., Department of Biochemistry, Bioinformatics and Computational Biology Unit, University of Pretoria, Pretoria, South Africa; Joubert, A., Department of Physiology, University of Pretoria, Pretoria, South Africa
In the present study, Autodock 4.0 was employed to discover potential carbonic anhydrase IX inhibitors that are able to interfere with microtubule dynamics by binding to the Colchicine binding site of tubulin. Modifications at position 2' of estrone were made to include moieties that are known to improve the antimitotic activity of estradiol analogs. 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10),15-tetraen-3-ol-17-one estronem (C9) and 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (C12) were synthesized and tested in vitro. Growth studies were conducted utilizing spectrophotometrical analysis with crystal violet as DNA stain. Compounds C9 and C12 were cytotoxic in MCF-7 and MDA-MB-231 tumorigenic and metastatic breast cancer cells, SNO non-keratinizing squamous epithelium cancer cells and HeLa cells after 48 h exposure. Compounds C9 inhibited cell proliferation to 50% of the vehicle-treated controls from 110 to 160nm and C12 at concentrations ranging from 180 to 220nm. Confocal microscopy revealed abnormal spindle morphology in mitotic cells. Cell cycle analysis showed an increase in the number of cells in the G 2/M fraction after 24h and an increase in the number of cell in the sub-G 1 fraction after 48h, indicating that the compounds are antimitotic and able to induce apoptosis. © 2011 John Wiley & Sons A/S.
2 ethyl 3 o sulphamoy lestra 1,3,5(10), 15 tetraen 3 ol 17 one estronem; 2 ethyl 3 o sulphamoyl estra 1,3,5(10) 16 tetraene; 3,4 methylenedioxyamphetamine; antimitotic agent; carbonate dehydratase inhibitor; colchicine; crystal violet; tubulin; unclassified drug; apoptosis; article; breast cancer; cancer cell culture; cancer inhibition; cell count; cell cycle G1 phase; cell cycle G2 phase; cell cycle M phase; cell fractionation; cell strain MCF 7; concentration (parameters); confocal microscopy; controlled study; cytotoxicity; drug binding site; drug screening; drug synthesis; HeLa cell; human; human cell; in vitro study; microtubule assembly; mitosis inhibition; mitosis rate; molecular docking; priority journal; spectrophotometry; squamous cell carcinoma; Antigens, Neoplasm; Antimitotic Agents; Binding Sites; Breast Neoplasms; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Division; Cell Line, Tumor; Colchicine; Computer Simulation; Drug Design; Estrone; Female; G2 Phase; Humans; Software; Tubulin