Synthesis of Tolmetin Hydrazide-Hydrazones and Discovery of a Potent Apoptosis Inducer in Colon Cancer Cells.
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, (1)H 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 76 μM 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.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, İstanbul, Turkey.
Ş Güniz
ŞG
Küçükgüzel
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, İstanbul, Turkey.
Derya
D
Koç
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, İstanbul, Turkey.
Pelin
P
Çıkla-Süzgün
Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, İstanbul, Turkey.
Derya
D
Özsavcı
Department of Biochemistry, Faculty of Pharmacy, Marmara University, Haydarpaşa, İstanbul, Turkey.
Özlem
Ö
Bingöl-Özakpınar
Department of Biophysics, School of Medicine, Marmara University, Başıbüyük, İstanbul, Turkey.
Pınar
P
Mega-Tiber
Department of Biophysics, School of Medicine, Marmara University, Başıbüyük, İstanbul, Turkey.
Oya
O
Orun
Department of Chemistry, Faculty of Arts and Sciences, Marmara University, Göztepe, Istanbul, Turkey.
Pınar
P
Erzincan
Department of Chemistry, Faculty of Arts and Sciences, Marmara University, Göztepe, Istanbul, Turkey.
Safiye
S
Sağ-Erdem
Department of Genetics and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, Kayışdağı, İstanbul, Turkey.
Fikrettin
F
Şahin
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051545:Cyclooxygenase 1 / Q000737:chemistry / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004789:Enzyme Activation; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014046:Tolmetin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D006835:Hydrazones; D014046:Tolmetin; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9
Apoptosis; Caspase-3; Colon cancer; Hydrazide-hydrazone; Tolmetin