PURPOSE: @entity22487 ( @entity6514 ) is a promising anti- @entity5 agent that disrupts the integrity and dynamics of the spindle network. In order to overcome the pharmacokinetic constraints of this compound, a panel of sulphamoylated @entity53 analogues were in silico-designed by our laboratory. In this study, we analysed the potential of each analogue to induce cell death on a panel of @entity5 cell lines. Moreover, the mechanism of action of the most effective compounds was determined. METHODS: @entity137 screening of the compounds and intermediates was performed on five different @entity5 cell lines to determine IG50 values. An in vitro tubulin polymerization assay was done to determine the effect of the drugs on tubulin polymerization while their intracellular effects on the microtubule network were assessed by immunofluorescence microscopy. RESULTS: IG50 calculations showed that the sulphamoylated analogues induce @entity137 at nanomolar concentrations in all cell lines, including the P-glycoprotein pump overexpressing multidrug-resistant uterine @entity242 cell line. The non-sulphamoylated compounds were only cytotoxic at micromolar ranges, if at all. The sulphamoylated compounds inhibited pure tubulin polymerization in a dose-dependent manner and induced microtubule destruction in cells after 24-h exposure. CONCLUSION: Results revealed that the novel sulphamoylated 2ME derivatives have potential as anti- @entity5 drugs, possibly even against chemoresistant @entity5 cells. These compounds disrupt the intracellular microtubule integrity which leads to mitotic block  of the cells.

Novel in silico-designed XXXX analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations.

@entity137 :: ('MESH:D064420', 'Disease') :: ['Cytotoxicity', 'cytotoxicity'] @entity242 :: ('MESH:D012509', 'Disease') :: ['sarcoma'] @entity5 :: ('MESH:D009369', 'Disease') :: ['cancer'] @entity53 :: ('MESH:D004958', 'Chemical') :: ['estradiol'] @entity6514 :: ('MESH:D008623', 'Chemical') :: ['2ME'] @entity22487 :: ('MESH:C022830', 'Chemical') :: ['2-Methoxyestradiol']
@entity53 :: (MESH:D004958,Chemical) :: ['estradiol']
