Abstract:
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 110-160
nM and C12 at concentrations ranging from 180-220 nM. Confocal microscopy revealed abnormal spindle
morphology in mitotic cells. Cell cycle analysis showed an increase in the number of cells in the G2/M
fraction after 24 h and an increase in the number of cell in the sub-G1 fraction after 48 h, indicating that
the compounds are antimitotic and able to induce apoptosis.
