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A series of A-ring variously methoxylated 4-(3-hydroxy-4-methoxyphenyl)coumarins related to combretastatin A-4 was prepared by cross-coupling reactions. Cytotoxicity studies indicated a potent activity against HBL100 cell line. Substitution patterns on A-ring had only a slight effect on antiproliferative activity. For most cytotoxic compounds, the activity as potential modulators of P-gp and BCRP efflux pumps was evaluated. The results show that compounds 2and 7were able to restore mitoxantrone accumulation (BCRP) at concentrations similar to that of cyclosporine A. Compound 7was the most efficient to reverse P-gp activity. All compounds were found to potently inhibit in vitro microtubule formation via a substoichiometric mode of action for the most part. Compounds 1and 2were found to have an apparent affinity binding constant similar to that of combretastatin A-4, i.e., 1 × 10 6M–1. The molecular modeling of coumarin derivatives was performed on the basis of the molecular structure of 7, as determined by single-crystal X-ray crystallography. The calculations suggested that the presence of a methoxy group out of the plane of the chromenone moiety is an important steric hindrance factor embedding the accessibility of those molecules inside the binding pocket on tubulin.