Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells

KÜÇÜKGÜZEL Ş. G., Koc D., Cikla-Suzgun P., ÖZSAVCI D., BİNGÖL ÖZAKPINAR Ö., MEGA TİBER P., ...More

Archiv der Pharmazie, vol.348, no.10, pp.730-742, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 348 Issue: 10
  • Publication Date: 2015
  • Doi Number: 10.1002/ardp.201500178
  • Journal Name: Archiv der Pharmazie
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.730-742
  • Keywords: Apoptosis, Caspase-3, Colon cancer, Hydrazide-hydrazone, Tolmetin, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, COLORECTAL-CANCER, ANTI-HCV, BIOLOGICAL-ACTIVITIES, PRO-APOPTOSIS, ASPIRIN USE, IN-VITRO, COX-2, DERIVATIVES, ANTICANCER
  • Marmara University Affiliated: Yes

Abstract

Tolmetin hydrazide and a novel series of tolmetin hydrazide-hydrazones 4a-l were synthesized in this study. The structures of the new compounds were determined by spectral (FT-IR, H-1 NMR) methods. N-[(2,6-Dichlorophenyl)methylidene]-2-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetohydrazide (4g) was evaluated in vitro using the MTT colorimetric method against the colon cancer cell lines HCT-116 (ATCC, CCL-247) and HT-29 (ATCC, HTB-38) to determine growth inhibition and cell viability at different doses. Compound 4g exhibited anti-cancer activity with an IC50 value of 76M against colon cancer line HT-29 (ATCC, HTB-38) and did not display cytotoxicity toward control NIH3T3 mouse embryonic fibroblast cells compared to tolmetin. In addition, this compound was evaluated for caspase-3, caspase-8, caspase-9, and annexin-V activation in the apoptotic pathway, which plays a key role in the treatment of cancer. We demonstrated that the anti-cancer activity of this compound was due to the activation of caspase-8 and caspase-9 involved in the apoptotic pathway. In addition, in this study, we investigated the catalytical effect of COX on the HT-29 cancer line, the apoptotic mechanism, and the moleculer binding of tolmetin and compound 4g on the COX enzyme active site.