Exploration of anti-tumor activity of erlotinib derivatives enabled by a Pd-catalyzed late-stage Sonogashira reaction

Fifty-eight erlotinib derivatives were designed and synthesized efficiently by the late-stage functionalization (LSF) strategy, directly installing the aryl, hetero aryl, and vinyl groups into the alkynyl group of the anticancer drug erlotinib. A new Palladium-NiXantphos catalyzed system of Sonogashira reaction was developed to accomplish the LSF of erlotinib. Both sp-sp2 coupling and sp-sp3 coupling could be achieved by the catalyst system. The reaction features mild, clean, high chemo-selectivity, and good functional group tolerance. Five compounds (3d, 3l, 5i, 5p, and 7c) showed potent cytotoxicity against A549 cancer cell lines. Compound 3l displayed excellent activity with IC50 11.4 μM, better than that of erlotinib (IC50 35.5 μM).