Investigation of metal based phenyl-functionalized pyridyl-triazolylidenes for their antitumor activity in vitro

Iako je u posljednjih nekoliko desetljeća učinjen velik napredak u rasvjetljavanju mehanizama nastanka zloćudnih bolesti i poboljšanju dijagnostičkih mogućnosti, tumori i dalje predstavljaju jedan od najvećih zdravstvenih problema današnjice. Kemoterapija je jedna od terapija koje se koriste u liječenju tumora. No, bez obzira na njenu uspješnost u liječenju pojedinih vrsta tumora, neželjene popratne pojave i pojava otpornosti tumora na kemoterapiju i dalje predstavljaju najveće izazove. U cilju smanjenja ili nadvladavanja navedenih nedostataka postoji stalna potreba za sintetiziranjem novih spojeva. Organometalni kompleksi na bazi različitih metala i kompozicija liganada pokazali su već protutumorska djelovanja. U ovom istraživanju korištenjem metode MTT (3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolij bromid) ispitana je razina citotoksičnosti dvanaest kompleksa: [(aren)M(fenil-functionalizirani piridil-1,2,3-triazol-5-iliden)klor] (M = iridij, osmij ili rutenij, aren = η(5)-1,2,3,4,5-pentametilciklopentadienil ili η(6)-p-cimen) na ljudskim stanicama karcinoma vrata maternice (HeLa). Kompleks s iridijem nazvan ABB43 pokazao je povećanu citotoksičnost, veću i od citostatika široke primjene, cisplatine. Citotoksičnost ABB43 je ispitana na još nekoliko tumorskih linija stanica različitog porijekla i na normalnoj staničnoj liniji. Povećana razina citotoksičnog učinka na tumorskim staničnim linijama u odnosu na normalnu staničnu liniju upućuje na potencijalno korištenje kompleksa kao protutumorskog lijeka. Protočnim je citometrom pokazano da ABB43 zaustavlja stanični ciklus u fazi S/G2 i inducira apoptozu. Specifičnom inhibicijom ili poticanjem sinteze staničnog glutationa (GSH) utvrđeno je da GSH igra ulogu u odgovoru stanica na stres izazvan tretmanom ABB43.Although there has been a great progress in elucidating the mechanisms of malignant diseases and the improvement in diagnostic methods, cancers remain one of the biggest health problem today. One of the cancer therapies is chemotherapy. However, despite its success in treating certain types of cancer, the resistance and the unwanted side effects are still representing the greatest challenges to this treatment. In order to reduce or overcome the above disadvantages there is a continuous need to synthesize new compounds. Organometallic complexes based on different metals and ligands have already showed anticancer activities. This research investigated the cytotoxic activity of twelve compounds: [(arene)M(phenyl-functionalized pyridyl-1,2,3-triazol-5-ylidene)chlor] (M = iridium, osmium or ruthenium, arene = 1,2,3,4,5- pentamethylcyclopentadienyl or p-cymen) in human cervix carcinoma cell line (HeLa) using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. Iridium(III) compound ABB43 showed higher cytotoxicity, even than cisplatin, the widely used cytostatic. ABB43 cytotoxicity was investigated in several other tumor cell lines and normal cell line. Higher cytotoxicity levels in tumor cell lines in regard to normal cell line indicate the potential use of the complex as anticancer drug. It was showen by flow cytometry that ABB43 blocks the S/G2 phase of the cell cycle and induces apoptosis. Specific inhibitors or stimulators of the synthesis of cellular glutathione (GSH) have showed that GSH plays a role in the cell response to stress caused by ABB43 treatment