Abstract
As a continuation of our efforts to optimize the antimitotic effect of our pyrimido[4,5-c]quinolin-1(2H)-one scaffold, we were interested in exploring the SAR of substituents at position 3 of this fused ring system. Target compounds 2a-r having substituents with diverse electronic and steric characteristics at the 3-phenyl ring were synthesized and tested for in vitro cytotoxicity against lung fibrosarcoma HT-1080 and colon adenocarcinoma HT-29 human cancer cell lines using the widely accepted MTT assay. Most of the compounds displayed cytotoxic effects in the low micromolar range. Clear-cut SAR conclusions were drawn from the available biological data. Generally, o-substitution results in a marked decrease or complete loss of cytotoxicity. Multimethoxy substitution in this particular position does not contribute to the cytotoxic effect but leads to cytotoxic selectivity for HT-1080 versus HT-29 cells. Interestingly, the best position for cytotoxicity of a halogen was the p-position, whereas m-substitution was the most favourable within the methyl/methoxy series. To confirm the mechanism of action previously identified for our closely related analogues, the most cytotoxic compounds were evaluated for their effects on cell cycle progression and tubulin polymerization. All compounds tested were found to arrest HT-1080 cells in the G2/M phase of the cell cycle and inhibit tubulin polymerization in a similar fashion to colcemid which is a known tubulin polymerization inhibitor.
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