Docking, synthesis, and in vitro evaluation of antimitotic estrone analogs.
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 160 nm and C12 at concentrations ranging from 180 to 220 nm. 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 24 h and an increase in the number of cell in the sub-G(1) fraction after 48 h, indicating that the compounds are antimitotic and able to induce apoptosis.
Department of Physiology, University of Pretoria, Pretoria, South Africa. standerandre@gmail.com
Andre
A
Stander
Fourie
F
Joubert
Annie
A
Joubert
D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry; D003198:Computer Simulation; D015195:Drug Design; D004970:Estrone / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D016195:G2 Phase; D006801:Humans; D012984:Software; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D000951:Antigens, Neoplasm; D050256:Antimitotic Agents; D002257:Carbonic Anhydrase Inhibitors; D014404:Tubulin; D004970:Estrone; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D003078:Colchicine