Structural, theoretical and antitumor investigation of dinuclear platinum(II) and palladium(II) complexes with aromatic N-heterocyclic bridging ligands

[A. Franich]

[6], 133, [5] listova

U okviru ove doktorske disertacije prikazana je sinteza dinuklearnih platina(II) i paladijum(II) kompleksa, [{M(en)Cl}2(μ-L)]2+ , M je Pt(II) ili Pd(II), en je bidentatno koordinovan etilendiamin, a L je mostni ligand 4,4ʼ-bipiridin (Pt1 i Pd1), 1,2-bis(4-piridil)etan (Pt2 i Pd2), 1,2-bis(4-piridil)etilen (Pt3 i Pd3), hinoksalin (Pd4), hinazolin (Pd5) i ftalazin (Pd6). Na osnovu rezultata elementalne mikroanalize, NMR (1H i 13C) i IR spektroskopije kao i UV-Vis spektrofotometrije potvrđena je struktura sintetisanih dinuklearnih kompleksa. Struktura Pt1-Pt3 kompleksa je potvrđena i na osnovu rezultata masene spektroskopije. Interakcije Pt1-Pt3 kompleksa sa CT-DNK ispitivane su primenom UV-Vis spektrofotometrije, fluorescentne i IR spektroskopije, merenjem viskoziteta, gel elektroforezom i molekulskim dokingom. Na osnovu dobijenih rezultata može se zaključiti da planarni 1,2-bis(4-piridil)etilen mostni ligand uslovljava interkalaciju Pt3 kompleksa u CT-DNK, dok se Pt1 i Pt2 kompleksi vezuju za fosfatne grupe DNK heliksa. Hidrolizom Pt1-Pt3 kompleksa nastaju Pt1W-Pt3W akva kompleksi koji se vezuju za DNK premošćavanjem malog žljeba. Rezultati UV-Vis spektrofotometrije, fluorescentne spektroskopije i merenje viskoziteta pokazuju da paladijum(II) kompleksi interkaliraju u CT-DNK gde mostni ligandi imaju važan uticaj na jačinu ostvarene veze. Pt1-Pt3 kompleksi prevazilaze rezistentnost ispitivanih ćelija kao i anti-angeogeni terapeutski potencijal sunitiniba, dok Pt3 kompleks pokazuje najveći citotoksični potencijal u odnosu na ispitivane ćelijske linije. In vitro ispitivanja citotoksičnog potencijala Pd1-Pd6 kompleksa pokazuju da ovi kompleksi izazivaju apoptozu ispitivanih ćelija sa smanjenom ekspresijom Ki-67, a na nekim ćelijama pokazuju bolju aktivnost od cisplatine.

In this doctoral dissertation is presented the synthesis of dinuclear platinum(II) and palladium(II) complexes, [{M(en)Cl}2(μ-L)]2+ , where M is Pt(II) or Pd(II), en is bidentate coordinated ethylenediamine, while L is bridging ligand 4,4ʼ-bipyridine (Pt1 and Pd1), 1,2-bis(4-pyridyl)ethane (Pt2 and Pd2), 1,2-bis(4-pyridyl)ethylene (Pt3 and Pd3), quinoxaline (Pd4), quinazoline (Pd5) and phthalazine (Pd6). The structure of synthesized dinuclear complexes was confirmed by elemental microanalysis, NMR (1H and 13C) and IR spectroscopy, as well as UV-Vis spectrophotometry. The structure of the Pt1-Pt3 complexes was also confirmed based on the results of mass spectroscopy. The interactions of the Pt1-Pt3 complexes with CT-DNA were investigated by UV-Vis spectrophotometry, fluorescence and IR spectroscopy, viscosity measurement, gel electrophoresis and molecular docking. Based on the obtained results of the mentioned methods, it can be concluded that the planar 1,2-bis(4-pyridyl)ethylene bridging ligand conditions the intercalation of the Pt3 complex in CT-DNA, while the Pt1 and Pt2 complexes bind to the phosphate groups of the DNA helix. Hydrolysis of the Pt1-Pt3 complex produced Pt1W-Pt3W aqua complexes that bind to DNA by the minor groove covering. The results of UV-Vis spectrophotometry, fluorescence spectroscopy and viscosity measurement showed that palladium(II) complexes intercalate in CT-DNA while bridging ligands have an important influence on the strength of the bond. Pt1-Pt3 complexes overcome the resistance of the tested cells as well as the anti-angiogenic therapeutic potential of sunitinib, while the Pt3 complex showed the highest cytotoxic potential against tested cell lines. In vitro investigation of cytotoxicity of the Pd1-Pd6 complexes showed that these complexes induce apoptosis of the examined cells with reduced expression of Ki-67, and on some tested cells complexes showed better activity than cisplatin.

546.922/.98-386(043.3)

Platina, dvovalentna - Kompleksna jedinjenja

Paladijum, dvovalentan - Kompleksna jedinjenja

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