Synthesis and bioactivity studies of covalent inhibitors derived from (-)-Chaetominine

•More than 34 new analogues of Chaetominine have been synthesized.•These new analogues feature versatile electrophilic warheads.•Some analogues show improved antitumor activities in cancer cell lines compared to Chaetominine. We reported herein the synthesis and bioactivity studies of compounds derived from the natural product (-)-Chaetominine (6). The key feature of these compounds is the incorporation of electrophilic groups that are capable of forming covalent bonds with the cysteine or threonine residues of cellular proteins. The cell growth inhibition activities of these derivatives of 6 were tested in four cancer cell lines, i.e. a leukemia cell line K562, a multiple myeloma cell line MM1.S, an acute myeloid leukemia cell line MV4-11, and a colon cancer cell line RKO. The data show that cellular growth inhibition IC50 values of 29, an acrylamide-containing molecule, are 9-17 folds more potent than that of 6, while other acrylamide-containing compounds are much less potent, suggesting 29 might have covalent interactions with cellular target proteins. Collectively, incorporation of an acrylamide moiety into 6 is a good strategy to improve its cell growth inhibition activity in cancer cell lines. [Display omitted]