Synthesis and cytotoxicity of some rigid derivatives of methyl 2,5-dihydroxycinnamate

Abstract

Eight rigid compounds designed as esterase-stable analogues of methyl 2,5-dihydroxycinnamate (1) were synthesized. These derivatives include 2-(2′,5′-dihydroxybenzylidene)cyclopentenone (3a), 2-(2′,5′-dihydroxybenzylidene)cyclohexanone (3b), 2,6-bis(2′,5′-dihydroxybenzy-lidene)cyclohexanone (4b), 2,6-bis(2′,5′-dihydroxybenzylidene)cyclopentenone (4a), (E)-3-(2′,5′-dihydroxybenzylidene)pyrrolidin-2-one (5), (E)-5-(2′,5′-dihydroxybenzylidene)-1,2-isothiazolidine-1,1-dioxide (6), 4-(2′,5′-dihydroxyphenyl)-5H-furan-2-one (7), and 3-(2′,5′-dihydroxyphenyl)cyclopent-2-ene-1-one (8). Among the eight compounds, the furanone 7 and cyclopentenone 8 showed the most potent cytotoxicity with IC50 values of 0.39-0.98 μg/mL. Compound 8 was further brominated, phenylated and methylated at the α position to give three corresponding analogues, including 2-bromo-3-(2′,5′- dihydroxyphenyl)cyclopent-2-ene-1-one (24), 3-(2′,5′- dihydroxyphenyl)-2-phenylcyclopent-2-ene-1-one (27), and 3-(2′,5′- dihydroxyphenyl)-2-methylcyclopent-2-ene-1-one (28). Among the three, the most enhanced activity was observed with the phenylated compound 27.