RESUMEN
Two novel halogenated (Br- and F-) quinazoline derivatives, namely [(E)-4-(2-((6-bromopyridin-2-yl)methylene)hydrazinyl)quinazoline] (L1) and [(E)-4-(2-((3-fluoropyridin-2-yl)methylene)hydrazinyl) quinazoline] (L2), were synthesized and characterized. Their interaction with a series of metal(II) ions (= Mn(II), Ni(II), Cu(II), Zn(II) and Cd(II)) resulted in the formation of six mononuclear complexes characterized by spectroscopic techniques and single-crystal X-ray crystallography. The complexes bear the formulae [Ni(L1)2](NO3)2 (1), [Zn(L2)2](NO3)(PF6) (2), [Cd(L2)(H2O)(CH3OH)(NO3)](NO3) (3), [Cu(L2)Cl2] (4), [Ni(L2)2](NO3)2 (5) and [Mn(L2)(CH3OH)(Cl)2] (6). The biological activity of the compounds was further evaluated in vitro regarding their interaction with calf-thymus DNA, their cleavage ability towards supercoiled circular pBR322 plasmid DNA in the absence or presence of irradiation at various wavelengths (UVA, UVB and visible light), their affinity to bovine serum albumin and their ability to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals and to reduce H2O2. In silico molecular docking calculations were employed to study the behavior of the complexes towards calf-thymus DNA and bovine serum albumin.
Asunto(s)
Complejos de Coordinación , Elementos de Transición , Albúmina Sérica Bovina/química , Antioxidantes/química , Simulación del Acoplamiento Molecular , Quinazolinas/farmacología , Cadmio , Peróxido de Hidrógeno , ADN/química , Cristalografía por Rayos X , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Cobre/químicaRESUMEN
The interaction of the recently reported quinazoline derivative (E)-4-(2-(pyridin-2-ylmethylene)hydrazinyl)quinazoline (L) with a series of metal(II) (= copper(II), nickel(II), cobalt(II) and cadmium(II)) chlorides or nitrates resulted in the formation of mononuclear complexes which were characterized by spectroscopic techniques and single-crystal X-ray crystallography, i.e. [Cu(L)2]Cl2·4H2O (1·4H2O), [Ni(L)2]Cl2·4H2O (2·4H2O), [Ni(L)2](NO3)2·MeOH (3·MeOH), [Co(L)2]Cl2·4H2O (4·4H2O), [Co(L)2](NO3)2·H2O (5·H2O), [Co(L)2](NO3)3·2.5H2O (6·2.5H2O), [Cd(L)(Cl)2]·H2O (7·H2O) and [Cd(L)(CH3OH)(H2O)(NO3)](NO3) (8). The biological profile of the complexes was further assessed in regard to their binding affinity with calf-thymus DNA, their cleavage ability towards pBluescript II KS plasmid DNA in the absence or presence of irradiation of various wavelengths, their interaction with bovine serum albumin and finally, their ability to scavenge 1,1-diphenyl-picrylhydrazyl and 2,2Î-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals and to reduce H2O2.
Asunto(s)
Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Quinazolinas/química , Quinazolinas/metabolismo , Animales , Antioxidantes/química , Antioxidantes/metabolismo , Benzotiazoles/metabolismo , Compuestos de Bifenilo/metabolismo , Cadmio/química , Bovinos , Cobalto/química , Cobre/química , Cristalografía por Rayos X/métodos , ADN/química , Humanos , Peróxido de Hidrógeno/metabolismo , Estructura Molecular , Níquel/química , Picratos/metabolismo , Unión Proteica , Albúmina Sérica Bovina/metabolismo , Ácidos Sulfónicos/metabolismoRESUMEN
The interaction of the novel quinazoline (E)-4-(2-(pyridin-2-ylmethylene)hydrazinyl)quinazoline (L) with Zn2+ was performed in the absence or presence of the non-steroidal anti-inflammatory drug sodium diclofenac (Nadicl) and resulted in the formation of complexes [Zn(L)2](NO3)2·MeOH (1·MeOH) and [Zn(L)(dicl-O)2]·MeOH (2·MeOH), respectively. The two complexes were characterized by IR and 1H NMR spectroscopy and by single-crystal X-ray crystallography. In these complexes, L was tridentately coordinated to Zn(II) via the quinazoline, hydrazone and pyridine nitrogen atoms. Further studies concerning the behavior of the compounds towards calf-thymus (CT) DNA and supercoiled circular pBluescript KS II plasmid DNA (pDNA) have been performed. The complexes may bind to CT DNA via intercalation, with complex 1 showing higher binding affinity than 2. The complexes may cleave pDNA in the absence or presence of irradiation with UVA, UVB or visible light and the most active pDNA-cleavager is compound 1. The binding constants of the compounds for bovine serum albumin were calculated and the subdomain of the albumin where the compounds prefer to bind was determined. The free radical scavenging ability of the compounds was evaluated towards 1,1-diphenyl-picrylhydrazyl and 2,2Î-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radicals with complex 2 being the most active compound. Thus, complex of type 1 maybe a lead compound for the development of novel DNA-binders and DNA-cleavers or photo-cleavers for medical and biotechnological "on demand" applications, whereas the structure of complex type 2 may provide novel antioxidants and radical scavengers.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , ADN/metabolismo , Diclofenaco/química , Compuestos de Zinc/química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Bovinos , Cristalografía por Rayos X/métodos , ADN/química , Diclofenaco/farmacología , Depuradores de Radicales Libres/química , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Albúmina Sérica Bovina/metabolismo , Compuestos de Zinc/farmacologíaRESUMEN
From the reaction of ZnCl2 with the non-steroidal anti-inflammatory drug diflunisal (Hdifl), complex [Zn(difl-O)2(MeOH)4], 1 was formed, while in the presence of a N,N'-donor heterocyclic ligand 2,2'-bipyridylamine (bipyam), 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen) and 2,2'-dipyridylketone oxime (Hpko), the complexes [Zn(difl-O,O')2(bipyam)], 2, [Zn(difl-O,O')2(bipy)], 3, [Zn(difl-O,O')2(phen)], 4 and [Zn(difl-O)2(Hpko)2], 5 were isolated, respectively. The complexes were characterized by physicochemical and spectroscopic techniques and the crystal structures of complexes 2, 3 and 5 were determined by X-ray crystallography. The ability of the complexes to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) and hydroxyl radicals and to inhibit soybean lipoxygenase was studied and the complexes were more active than free Hdifl. The interaction of the complexes with serum albumins was monitored by fluorescence emission spectroscopy and the corresponding binding constants were calculated. UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for the competitive studies of the complexes with ethidium bromide were employed to investigate the interaction of the complexes with calf-thymus DNA and revealed intercalation as the most possible DNA-binding mode. Computational techniques were used to identify possible binding sites of albumins and DNA, and determine the druggability of human and bovine serum albumins with the five novel complexes. The majority of the complexes are stronger binders than the free Hdifl. This is the first study incorporating experimental and computational results to explore the binding activity of metal-NSAID complexes with DNA and serum albumins, suggesting their application as potential metallodrugs.