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Square planar compounds containing 3,3-biisoquinoline: synthesis and G-quadruplexes DNA binding studies

Grant number: 13/26203-5
Support type:Scholarships abroad - Research
Effective date (Start): August 01, 2014
Effective date (End): March 31, 2015
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Adelino Vieira de Godoy Netto
Grantee:Adelino Vieira de Godoy Netto
Host: Michael John Hannon
Home Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : University of Birmingham, England  

Abstract

This work deals with the synthesis, characterization and human telomeric G-quadruplex DNA binding studies on new chelates of general formulae [M(bisq)(N-X)]+n (M = Pd(II), Pt(II); bisq = 3,32-biisoquinoline; N-X (X = C) = C2,N-benzylidenemethylamine, C2,N-benzaldehydeoxime type-ligands; N-X (X = S) = thiosemicarbazide type ligands; n = 1,2). These complexes exhibit pre-conceived structural requirements suitable for acting as telomeric G-quadruplex DNA binders and, eventually, as new anti-telomerase agents. The characterization of the functionalized ligands and their metal-based derivatives will be carried out by elemental analysis, IR and NMR spectroscopies, ESI/MS spectrometry, and single crystals X-ray diffraction crystallography. Selectivity for G-quadruplexes (G4-DNA) over duplex DNA structures (dsDNA) will be evaluated by determining the intrinsic DNA binding constants (Kb) via UV-Vis spectroscopy. Circular dicroism will be obtained in order to evidence topology adopted by G4 and to verify if the complex contributes to the formation and stabilization of G-4 structure. The affinity of the complexes for G4-DNA over dsDNA will be evaluated by the required concentration to displace 50% of thiazole orange (G4DC50 and dsDC50, respectively) using the Fluorescent Intercalator Displacement assay (FID) and the selectivity will be estimate by the dsDC50/G4DC50 ratio. Electrophoresis mobility shift assays will be employed to determine conformational changes in DNA, including the formation or destabilization of a quadruplex, and the binding between ligands and quadruplexes. The citotoxicity of compounds towards tumor cell sensitive (ex. A2780) and resistant to cisplatin (ex. A2780cisR) will be determined by M.T.T. assay. (AU)