Water-soluble DNA minor groove binders as potential chemotherapeutic agents: synthesis, characterization, DNA binding and cleavage, antioxidation, cytotoxicity and HSA interactions

Two new water-soluble copper(ii)-dipeptide complexes: [Cu(glygly)(PyTA)]ClO4·1.5H2O (1) and [Cu(glygly)(PzTA)]ClO4·1.5H2O (2) (glygly = glycylglycine anion, PyTA = 2,4-diamino-6-(2'-pyridyl)-1,3,5-triazine and PzTA = 2,4-diamino-6-(2'-pyrazino)-1,3,5-triazine), utilizing two interrelated D...

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Published in:Dalton transactions : an international journal of inorganic chemistry 2014-06, Vol.43 (23), p.8721-8737
Main Authors: Fu, Xia-Bing, Liu, Dan-Dan, Lin, Yuan, Hu, Wei, Mao, Zong-Wan, Le, Xue-Yi
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antioxidants - chemical synthesis
Antioxidants - chemistry
Antioxidants - pharmacology
Binding Sites - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Copper - chemistry
Crystallography, X-Ray
DNA - chemistry
DNA - drug effects
DNA Cleavage
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HeLa Cells
Hep G2 Cells
Humans
Models, Molecular
Molecular Structure
Organometallic Compounds - chemical synthesis
Organometallic Compounds - chemistry
Organometallic Compounds - pharmacology
Plasmids
Serum Albumin - chemistry
Solubility
Structure-Activity Relationship
Water - chemistry
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Summary:Two new water-soluble copper(ii)-dipeptide complexes: [Cu(glygly)(PyTA)]ClO4·1.5H2O (1) and [Cu(glygly)(PzTA)]ClO4·1.5H2O (2) (glygly = glycylglycine anion, PyTA = 2,4-diamino-6-(2'-pyridyl)-1,3,5-triazine and PzTA = 2,4-diamino-6-(2'-pyrazino)-1,3,5-triazine), utilizing two interrelated DNA base-like ligands (PyTA and PzTA), have been synthesized and characterized. The structure elucidation for 1 performed by single crystal X-ray diffraction showed a one dimensional chain conformation in which the central copper ions arrange in a five-coordinate distorted square-pyramidal geometry. Spectroscopic titration, viscosity and electrophoresis measurements revealed that the complexes bound to DNA via an outside groove binding mode, and cleaved pBR322 DNA efficiently in the presence of ascorbate, probably via an oxidative mechanism with the involvement of ˙OH and ˙O2(-). Notably, the complexes exhibited considerable in vitro cytotoxicity against four human carcinoma cell lines (HepG2, HeLa, A549 and U87) with IC50 values ranging from 41.68 to 159.17 μM, in addition to their excellent SOD mimics (IC50 ~ 0.091 and 0.114 μM). Besides, multispectroscopic evidence suggested their HSA-binding at the cavity containing Trp-214 in subdomain IIA with moderate affinity, mainly via hydrophobic interaction. Further, the molecular docking technique utilized for ascertaining the mechanism and mode of action towards DNA and HSA theoretically verified the experimental results.
ISSN:1477-9226
1477-9234
DOI:10.1039/c3dt53577k