Synthesis, characterization and biological activity of mono- and dinuclear ruthenium(II/III) complexes with nitrogen-donor ligands

[M. M. Stefanović]

[11], 145, [7] listova

U okviru disertacije opisana je sinteza novih mononuklearnih Ru(II) (1–7) i Ru(III) kompleksa (8–13), kao i dinuklearnih Ru(II) kompleksa (14, 15). Strukture kompleksa potvrđene su analitičkim metodama, kao što su UV-Vis spektrofotometrija, 1H i 13C NMR, IR, MS, EPR, merenje provodljivosti i elementalna mikroanaliza. Proučavani kompleksi pokazali su dobru stabilnost u fiziološkim uslovima, čime su se stekli uslovi za dalja istraživanja. U supstitucionim reakcijama kompleksi rutenijuma 1–7, 14 i 15 pokazali su veću reaktivnost prema azot-donorskim (5'-GMP) nego prema sumpor-donorskim nukleofilima (GSH, L-Met i L-Cys). Rezultati ispitivanja interakcija kompleksa sa DNA ukazali su na vezivanje interkalacijom i/ili vezivanjem za mali žljeb, što je potvrđeno i na 1Z3F i 1BNA konformacijama DNA kompjuterskim doking metodama. Ispitivani kompleksi pokazali su umerenu jačinu vezivanja (Kb = 104 – 106 ) za protein HSA i njegov strukturni analog BSA. Molekulski doking je kod dinuklearnih kompleksa 14 i 15 izdvojio aktivno mesto I subdomena IIA kao verovatno, dok je kod mononuklearnih kompleksa 1–13 potvrđena mogućnost vezivanja za mesto I subdomena IIA i za mesto II subdomena IIIA aktivne strane proteina. Rezultati ispitivanja biološke aktivnosti ukazali su na dobru aktivnost i selektivnost kompleksa 2, 5 i 6 prema MDA-MB 231 i HeLa ćelijskim linijama. Kompleks 12 pokazao se efikasnim u smanjenju tumora pluća, a kompleks 9 u smanjenju broja metastaza. Kompleks 15 pokazao se aktivnijim u poređenju sa kompleksom 14 prema MDA-MB-231 ćelijskoj liniji, dok su se prema HCT-116 ćelijskoj liniji pokazali neaktivnim. Na kompjuterskom doking modelu pankreasa proučavana difuzija kompleksa 8–13 kroz tkiva i velike krvne sudove dala je jasan uvid u njihov farmaceutski potencijal. In vitro ispitivanja antimikrobne aktivnosti izdvojila su komplekse 12 i 13 kao najefikasnije, dok se po antioksidativnim svojstvima izdvojio kompleks 8.

This doctoral dissertation describes the synthesis of new mononuclear Ru(II) (1–7) and Ru(III) (8–13) complexes as well as dinuclear ruthenium(II) complexes (14 and 15). The structures of complexes were confirmed by various analytical methods, such as UV-Vis, 1H and 13C NMR, IR, EPR, ESI-MS spectroscopy, conductivity measurements and elemental microanalysis. These complexes showed good stability in physiological conditions and thus became suitable candidates for further research. Ruthenium complexes 1-7, 14 and 15 were more reactive towards nitrogen-donor nucleophiles (5’-GMP) than toward sulfur-donor nucleophiles (GSH, L-Cys and L-Met) in the nucleophilic substitution reactions. Results obtained from the examination of the interactions of ruthenium complexes with DNA indicated binding by intercalation and/or minor groove binding, which was also confirmed by computational docking methods on two DNA conformations, 1Z3F and 1BNA. Ruthenium complexes bind to both sites with moderately strong affinity (Kb = 104 – 106 M−1 ) to HSA and its structural analogue BSA. Molecular docking of dinuclear complexes 14 and 15 singled out active site I of subdomain IIA as probable, while mononuclear complexes 1–13 confirmed the possibility of binding to active site I subdomain IIA and active site II subdomain IIIA of proteins. Complexes 2, 5 and 6 showed good to strong and highly selective cytotoxic activity on the MDA-MB 231 and HeLa cell lines. Furthermore, complex 12 reduced the volume of mouse primary heterotopic Lewis lung cancer, while complex 9 reduced the number of metastases per lung. Finally, dinuclear complex 15 was more active against MDA-MB-231 cells than complex 14. On computational pancreatic model we studied diffusion of complexes 8-13 through both tissue and large blood vessel domains, demonstrating that these complexes are promising candidates for future pharmacological research in the field of pancreatic adenocarcinoma research. In vitro investigation stands out complexes 12 and 13 for the best antibacterial activity, while complex 8 was singled out for its antioxidant properties.

• Rutenijum(II/III) kompleksi • Mehanizam supstitucije • Interakcije • DNA • BSA/HSA • Citotoksičnost • Molekulski doking

• Ruthenium(II/III) complexes • Mechanism of substitution • Interactions • DNA • BSA/HSA • Cytotoxicity • Molecular docking

546.96:576.382(043.3)

Molekularna biologija

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