Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines

Abstract

Variously substituted 2-hydroxy-N-(arylalkyl)benzamides were prepared and screened for antiproliferative and cytotoxic activity in cancer cell lines in vitro. Five compounds, out of 33 showed single-digit micromolar IC50 values against several human cancer cell lines. One of the most potent compounds N-((R)-1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (6k) reduced proliferation and induced apoptosis in the melanoma cell line G361 in a dose-dependent manner, as shown by decrease in 5-bromo-2'-deoxyuridine incorporation and increase in several apoptotic markers, including subdiploid population increase, activation of caspases and site-specific poly-(ADP-ribose)polymerase (PARP) cleavage.

Keywords: 1-hydroxybenzotriazole hydrate; 5-bromo-2′-deoxyuridine; Apoptosis; Autophagy; B-cell lymphoma 2; B-cell lymphoma-extra large; Bcl-2; Bcl-xL; BrdU; CDK; Cancer; Cbz; Cytotoxicity; DCC; DCM; DMF; Diamides; EDC·HCl; ERK1/2; Et(2)O; Et(3)N; EtOAc; GSK; HMGB1; HOBt·H(2)O; IC(50); LC3; Mdm2; N,N′-dicyclohexylcarbodiimide; N,N′-dimethylformamide; N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; PARP-1; PET; RT; Rb; SAR; benzyloxycarbonyl group; cyclin-dependent kinase; dichloromethane; diethylether; ethyl acetate; extracellular-signal-regulated kinases; glycogen synthase kinase; growth inhibition 50%; high-mobility group protein B1; microtubule-associated protein light chain 3; mouse double minute 2; p53; photosynthetic electron transport; poly-(ADP-ribose)polymerase-1; retinoblastoma protein; room temperature (approx. 20 °C); structure–activity relationship; triethyl amine.