Design of copper DNA intercalators with leishmanicidal activity

a b s t r a c tThe mono and bis dipyrido[3,2-a:2 0 ,3 0 -c]phenazine (dppz) adducts of iron(III) chloride, i.e. [Fe(dppz)]Cl 3 and [Fe(dppz) 2 ]Cl 3 , have been synthesized and characterized. The interaction of the Fe III dppz hydrolyzed aquo complex with native calf thymus DNA has been monitored as a function of the metal complex-DNA molar ratio, by variable temperature UV absorption spectrophotometry, circular dichroism (CD) and fluorescence spectroscopy. The results obtained in solution at various ionic strength values give support for a tight intercalative binding of the Fe III dppz cation with DNA. In particular, the appearance of induced CD bands, caused by the addition of Fe III dppz, indicate the existence of a rigid metal complex-DNA-binding leading to dominating chiral organization of Fe III dppz species within the DNA double helix. The trend of selected CD bands with the molar concentration of Fe III dppz emphasizes that the presence of high amounts of metal complex induces also the formation of DNA-Fe III dppz supramolecular aggregates in solution. The analysis of fluorescence measurements allowed us to calculate a value of the intercalative binding constant comparable to that obtained by UV spectrophotometric titration. Finally, the temperature dependence of the absorbance at 258 nm shows that the metal complex strongly increases the DNA melting temperature already at metal complex-DNA molar ratio equal to 0.25 suggesting that metal complex intercalation effectively hinders DNA denaturation. Overall, the results of the present study point out that the Fe III dppz aquo complex has DNA-binding properties analogous to those previously reported for the tris-chelate Fe II (phen) 2 dppz complex (phen = 1,10-phenantroline).

Section: Uv-vis Absorption Spectroscopymentioning

confidence: 85%

Section: Introductionmentioning

confidence: 84%

Section: Uv-vis Absorption Spectroscopymentioning

confidence: 99%

See 1 more Smart Citation

The interaction of native calf thymus DNA with FeIII-dipyrido[3,2-a:2′,3′-c]phenazine

Terenzi

Barone

Silvestri

et al. 2009

“…In particular, copper(II) complexes in the presence of oxidizing or reducing agents are able to cleave DNA. Research on DNA cleavage by synthetic copper complexes is of considerable interest because of their efficacy as anti-tumour agents [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

The interaction of native DNA with Zn(II) and Cu(II) complexes of 5-triethyl ammonium methyl salicylidene orto-phenylendiimine

Silvestri

Barone

Ruisi

et al. 2007

106

The interaction of native calf thymus DNA with the Zn(II) and Cu(II) complexes of 5-triethyl ammonium methyl salicylidene ortophenylendiimine (ZnL 2+ and CuL 2+ ), in 1 mM Tris-HCl aqueous solutions at neutral pH, has been monitored as a function of the metal complex-DNA molar ratio by UV absorption spectrophotometry, circular dichroism (CD) and fluorescence spectroscopy. The results support for an intercalative interaction of both ZnL 2+ and CuL 2+ with DNA, showing CuL 2+ an affinity of approximately 10 times higher than ZnL 2+ . In particular, the values of the binding constant, determined by UV spectrophotometric titration, equal to 7.3 · 10 4 and 1.3 · 10 6 M À1 , for ZnL 2+ and CuL 2+ , respectively, indicate the occurrence of a marked interaction with a binding size of about 0.7 in base pairs. The temperature dependence of the absorbance at 258 nm suggests that both complexes strongly increase the DNA melting temperature (Tm) already at metal complex-DNA molar ratios equal to 0.1. As evidenced by the quenching of the fluorescence of ethidium bromide-DNA solutions in the presence of increasing amounts of metal complex, ZnL 2+ and CuL 2+ are able to displace the ethidium cation intercalated into DNA. A tight ZnL 2+ -DNA and CuL 2+ -DNA binding has been also proven by the appearance, in both metal complex-DNA solutions, of a broad induced CD band in the range 350-450 nm. In the case of the CuL 2+ -DNA system, the shape of the CD spectrum, at high CuL 2+ content, is similar to that observed for w-DNA solutions. Such result allowed us to hypothesize that CuL 2+ induces the formation of supramolecular aggregates of DNA in aqueous solutions.

“…Such compounds, in particular [Ru(phen) 2 dppz] 2+ , have been recently used in cellular imaging studies and for virus tracking [23]. Indeed, all known metal complexes of dppz, independently of the nature of the ancillary ligands, are strong intercalating agents, with values of DNA-binding constants within 10 4 -10 7 M −1 [14,[24][25][26][27][28]. Furthermore, it has been recently shown that a cationic derivative of the dppz ligand shows analogous water solubility and DNA-binding constant of the mentioned dppz metal complexes [29,30].…”

Section: Introductionmentioning

confidence: 99%

(Dipyrido[3,2-a:2′,3′-c]phenazine)(glycinato)copper(II) perchlorate: A novel DNA-intercalator with anti-proliferative activity against thyroid cancer cell lines

Terenzi

Tomasello

Spinello

et al. 2012

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. A novel copper(II) heteroleptic complex of dipyrido[3,2-a:2′,3′-c]phenazine (dppz) and glycinato (gly) as chelating ancillary ligand, [Cu(dppz)(gly)]ClO 4 (1), was synthesized and characterized. X-ray crystallography revealed that the coordination geometry of the cationic [Cu(dppz)(gly)]+ unit is hexacoordinated and shows a distorted octahedral coordination geometry in the solid state, with the N,N and N,O chelating atoms of dppz and glycinato, respectively, in the square plane and in which the planar units are connected in a monodimensional polymeric array by the apical copper coordination of the second carboxylic oxygen atom. Biological assays showed that 1 exhibits a remarkable anti-proliferative activity against the two human anaplastic thyroid cancer cell lines 8505c (BrafV600E/V600E) and SW1736 (BrafWT/V600E), in a dose-and time-dependent manner. In details, the IC 50 after 48 h of drug exposure was 2.86±0.54 μM for SW1736 and 1.05±0.48 μM for 8505c. On the other hand, the IC 50 shown by cis-diamminedichloroplatinum(II) (cisplatin) against the same cell lines was 2.50±0.40 μM and 6.03±0.78 μM, respectively. Optical microscopy observations, after 48 h of treatment, showed morphological cell changes typical of apoptosis, confirmed by DNA ladder assays. DNA interaction studies, performed by UV absorption spectrophotometry, circular dichroism and viscosimetry, clearly showed that [Cu(dppz)(gly)]ClO 4 is a DNA-intercalator, with a DNA-binding constant, K b , of 2.1×10 6 M −1, suggesting that the mechanism of the cytotoxic activity can be related to its DNA-binding.