Chiral heterobimetallic complexes targeting human DNA-topoisomerase Iα

Abstract

The chiral monometallic Cu(II) (1) and Zn(II) (2) and heterobimetallic Cu(II)-Sn(IV) and Zn(II)-Sn(IV) complexes with tridentate chiral Schiff base -ONO-ligand in the presence of nitrogen donor heterocyclic ligand imidazole; were prepared and characterized by various physico-chemical and spectroscopic methods. Preliminary complex-DNA interaction studies employing optical methods revealed that 3 displayed a higher propensity towards the drug target DNA double helix and recommended predominantly an electrostatic mode of interaction as well as a groove binding affinity of the complex with CT-DNA. This was quantified by Kb and KSV values of complexes 1-4, which demonstrated a multifold increase in complex 3 binding to CT DNA and clearly demonstrates its potency to act as a chemotherapeutic agent. Furthermore, the gel electrophoretic patterns of supercoiled pBR322 DNA with varying concentrations of complex 3 exhibits the ability to cleave DNA and follow a freely diffusible radical mechanism. The antiproliferative effects of complex 3 on human hepatoma cancer cells (Huh7) was investigated. Human Topo I inhibition assay by complex 3 was performed and results confirmed significantly good activity at lower concentrations than some of the classical Topo I inhibitors. Additionally, complex 3 was investigated for the expression of MMP-2 and TGF-β by real time PCR. The cellular uptake of complex 3 by HeLa cells was studied by confocal microscopy.

Synthesis, structure, spectral characterization and DNA binding affinity of new water soluble trinuclear copper(II) complexes with partial cubane Cu3O4 cores

“…The weak binding interaction of the complexes with DNA is most possibly due to the anionic nature of the complexes. The observed binding constant values are comparable to that of some copper(II) clusters reported in the literature [19,23].…”

“…Several tridentate [O 2 N] or [ON 2 ] donor set ligands have readily afforded trinuclear copper(II) complexes with [Cu 3 O] core [13][14][15][16]. There are some mono-and dinuclear copper(II) complexes reported in the literature that promote binding and cleavage of biomolecules such as DNA and protein [17][18][19][20]. Sorenson potential of copper(II) complexes in animal models [21].…”

Heteroleptic Copper(I) Complexes of “Scorpionate” Bis-pyrazolyl Carboxylate Ligand with Auxiliary Phosphine as Potential Anticancer Agents: An Insight into Cytotoxic Mode

“…Since circular dichroism (CD) is a technique highly sensitive to changes in the conformation of the chiral structure of DNA5255, it can be used to study the subtle variations upon its interaction with small molecules56575859. The CD spectrum of CT-DNA exhibits a positive band at 275 nm (UV, λ max  = 260 nm) caused by base stacking between the compounds and DNA, and a negative band at 245 nm caused by helicity, which is characteristic of DNA in right-handed B form.…”

“…10b)6263. Thus, we treated pBR322 DNA and complex 1 (10 μM) with hydroxyl radical scavengers (lane 1, DMSO and lane 2, EtOH), singlet oxygen quencher (NaN 3 , lane 3) and superoxide oxygen scavenger (SOD, lane 4), under identical conditions as above.…”

Organotin(IV) derivatives with 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidine and their cytotoxic activities: The importance of being conformers

“…Chirality thus generated in crystal packing is certainly a very important aspect in determining stereoselective and stereospecific interaction with target molecules [24] while an increased bio-activity may be hypothesized due to the multifaceted binding mode of conformers. Actually, due to the recent serendipitous discovery of aspirin form II [25,26] polymorphism in pharmaceutical chemistry has gained new impulse [27,28].…”