Antitumor and antimicrobial activity of newly synthesized platinium(II) and palladium(II) complexes

[S. Ž. Zornić]

114 listova

Kompleksi platine (Pt) i paladijuma (Pd) predstavljaju veliku grupu potencijalnih kandidata za razvoj antitumorske i antimikrobne terapije. U ovoj studiji sintetisani su dinuklearni kompleksi Pt(II) sa piridazinom kao mostnim ligandom i dinuklearni kompleksi Pd(II) sa aromatičnim N-heterocikličnim mostnim ligandima i analizirane njihove strukturne osobine i biološka aktivnost. Evaluacija tumoricidne aktivnosti kompleksa Pt(II) i Pd(II) ukazala je na varijabilan citotoksički efekat na različitim linijama tumorskih ćelija mišjeg i humanog porekla, kao i potencijalno manju toksičnost u poređenju sa cisplatinom. Kompleksi Pt(II) i Pd(II) su pokazali umeren antibakterijski i antigljivični efekat u zavisnosti od hemijske strukture i vrste mikroorganizma. Najveću dozno i vremenski zavisnu tumoricidnu aktivnost na ćelijama mišjeg i humanog karcinoma dojke in vitro, ispoljio je kompleks [{Pt(ibn)Cl}2(-pydz)]Cl2 (gde je ibn izobutilendiamin, a pydz piridazin), označen kao S2. Kompleks S2 indukuje unutrašnji put apoptoze ćelija karcinoma dojke što je dokumentovano povećanjem ekspresije kaspaze 9 i kaspaze 3. Antiproliferativni efekat kompleksa S2 ogleda se u smanjenju ekspresije regulatora ćelijskog ciklusa ciklina E i ciklina D3 i povećanju ekspresije inhibitora r27. Proapoptotski i antiproliferativni efekat kompleksa S2 je posledica smanjene ekspresije fosforilisane protein kinaze AKT i sledstveno onkogena s-Myc. Međutim, efekat kompleksa S2 na rast mišjeg karcinoma dojke in vivo je izostao, što se može objasniti slabim vezivanjem za netransportno mesto proteina i ograničenim dopremanjem u tumorsko tkivo. Validan tumoricidni i antimikrobni potencijal kompleksa Pt(II) i Pd(II) ukazuje na mogućnost daljih modifikacija u cilju poboljšanja biološke aktivnosti i potencijalne terapijske primene.

Platinum (Pt) and palladium (Pd) complexes are a large group of potential candidates for the development of antitumor and antimicrobial therapy. In this study, dinuclear Pt(II) complexes with pyridazine bridging ligand and dinuclear Pd(II) complexes with aromatic N-heterocyclic bridging ligands were synthesized and their structural properties and biological activity were analyzed. Evaluation of Pt(II) and Pd(II) complexes tumoricidal activity indicated variable cytotoxic effects on different mouse and human tumor cell lines, and potentially lower toxicity compared to cisplatin. Pt(II) and Pd(II) complexes showed moderate antibacterial and antifungal effects depending on the chemical structure and microorganism species. Complex [{Pt(ibn)Cl}2(- pydz)]Cl2 (ibn is isobutylenediamine and pydz is pyridazine), marked as C2, exhibited the highest dose- and time-dependent tumoricidal activity on mouse and human breast cancer cells in vitro. Complex C2 induces the intrinsic pathway of breast cancer cells apoptosis, documented by elevated caspase 9 and caspase 3 expression. Antiproliferative effect of complex C2 is reflected in the decreased expression of cell cycle regulators cyclin E and cyclin D3 and the increased expression of inhibitor p27. Proapoptotic and antiproliferative effects of complex C2 are consequences of reduced expression of phosphorylated AKT kinase and c-Myc oncogene. However, the effect of complex C2 on mouse breast cancer growth was absent, which can be explained by weak binding to the non-transport site of the protein and limited delivery to tumor. The valid tumoricidal and antimicrobial potential of Pt(II) and Pd(II) complexes indicates the possibility of further modifications in order to improve biological activity and potential therapeutic application.

dinuklearni kompleksi Pt(II), dinuklearni kompleksi Pd(II), tumoricidna aktivnost, antimikrobna aktivnost, apoptoza

dinuclear Pt(II) complexes, dinuclear Pd(II) complexes, tumoricidal activity, antimicrobial activity, apoptosis

616-097

Mikrobiologija

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