Chiral heterobimetallic complexes targeting human DNA-topoisomerase Iα.
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.
Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India. tsartaj62@yahoo.com.
Sartaj
S
Tabassum
Ahmad
A
Asim
Rais Ahmad
RA
Khan
Zahid
Z
Hussain
Saurabh
S
Srivastav
Saripella
S
Srikrishna
Farukh
F
Arjmand
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D012545:Schiff Bases / Q000737:chemistry; D014001:Tin / Q000737:chemistry / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D012545:Schiff Bases; D014001:Tin; D003300:Copper; D004247:DNA; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D015032:Zinc