A series of 19 analogues of the antiproliferative naphthopyran LY290181 were prepared for structure-activity relationship studies. We found the best activities for test compounds bearing small substituents at the meta position of the phenyl ring. The mode of action of LY290181 and eight new analogues was studied in detail. The compounds were highly anti-proliferative with IC50 values in the sub-nanomolar to triple-digit nanomolar range. The new analogues led to G2/M arrest due to interruption of the microtubule dynamics. In 518A2 melanoma cells they caused a mitotic catastrophe which eventually led to apoptosis. The naphthopyrans also induced a disruption of the vasculature in the chorioallantoic membrane (CAM) of fertilized chicken eggs as well as in xenograft tumors in mice. In a preliminary therapy trial, the difluoro derivative 2b retarded the growth of resistant xenograft tumors in mice.
Keywords: CAM assay; Microtubule destabilizing agents (MDA); Naphthopyrans; Vascular-disrupting agents (VDA).
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