Novel N-arylamide derivatives of (S)-perillic acid ((S)-PA): in vitro and in vivo cytotoxicity and antitumor evaluation

Hepatocellular carcinoma (HC) and glioblastoma (GBA) are the most commonly aggressive malignant liver and brain tumors. Based on an established method for the synthesis of amide, two novel analogues (4 and 5) of (S)-perillic acid were synthesized and their structures were affirmed using nuclear magnetic resonance spectroscopic analysis. An MTT cytotoxic assay showed that our derivatives (4 and 5) demonstrated a substantial anti-proliferative effect against HC (HepG2) and GBA (U251) cell lines. Particularly, compound 5 showed growth inhibitory (IC(50)) effects on U251 (IC(50) = 3.10 ± 0.12 μg mL(−1)) and HepG2 cells (IC(50) = 1.49 ± 0.43 μg mL(−1)), which fall within the acceptable standard recommended by the National institute of cancer (Bethesda, MD, USA) for the selection of anticancer drug candidates. Consequently, we assessed the in vivo antitumor and organ/tissue toxicity of 4, 5 and 5-fluorouracil (5-FU) in hepatoma H22-inoculated mice. The results obtained indicated remarkable tumor growth inhibition with no substantial toxicological effects on the mice and the organs/tissues in the treated groups compared well with the control.