Synthesis anticancer activity and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors

Abstract

A series of (RS)-1-{[5-(substituted)sulfanyl-4-substituted-4H-124-triazole-3-yl]methyl}-18-diethyl-1349-tetrahydropyrano[34-b]indoles (5a-v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (RS)-5-[(18-diethyl-1349-tetrahydropyrano[34-b]indole-1-yl)methyl]-4-substituted-24-dihydro-3H-124-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) colorimetric method against VERO HEPG2 (human hepatocellular liver carcinoma) SKOV3 (ovarian carcinoma) MCF7 (human breast adenocarcinoma) PC3 and DU145 (prostate carcinoma) cells at 10(-5)M (10M) for 24h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50=7.22 and 5.10M respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k 5s and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50=8.18 3.10 and 4.00M respectively) and did not display cytotoxicity. Moreover these compounds were evaluated for caspase-3 -9 and -8 protein expression and activation in the apoptosis pathway for 6 12 and 24h which play a key role in the treatment of cancer. In this study we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.