Rapid synthesis of 4-arylchromenes from ortho-substituted alkynols: A versatile access to restricted isocombretastatin A-4 analogues as antitumor agents
2015
Abstract Potent anticancer 4-arylchromene agents 6 , as restricted iso CA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substituted 4-chromanones 10 in a one pot procedure which include regioselective arylalkynols hydration, alcohol etherification, MOM-cleavage, and cyclization. Further palladium coupling reactions, using aryl halides and N -tosylhydrazones 11 gave access to a small library of functionalized 4-arylchromenes 6 with good yields. From this series of 4-arylchromenes, we have identified compound 6s which inhibit tubulin assembly at a micromolar level and demonstrate a remarkable nanomolar level of cytotoxicity against four human cancer cell lines. Docking studies showed that iso CA-4 and its restricted chromene analogue 6s adopt a similar positioning in the colchicine binding-site of tubulin.
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