325148-41-2Relevant academic research and scientific papers
Long-range distance constraints in platinated nucleotides: Structure determination of the 5′ orientational isomer of cis-[Pt(NH3)(4-aminoTEMPO){d(GpG)}]+ from combined paramagnetic and diamagnetic NMR constraints with molecular modeling
Dunham, Stephen U.,Lippard, Stephen J.
, p. 10702 - 10712 (1995)
The compound cis-[Pt(NH3)(4-aminoTEMPO)C1I] (7) is a paramagnetic analogue of the anticancer drug cisplatin and of cis-[Pt(NH3)(C6H11]NH2)Cl 2] (1), a major metabolite of a recently developed, orally administered derivative. The bifunctional mixed amine complex 7 and a monofunctional triamine complex, trarts-[Pt(NH3)2(4-aminoTEMPO)Cl]NO3 (8), were synthesized to provide localized unpaired electron spin density for use in NMR spectral studies of their polynucleotide adducts. Compounds 7 and 8 readily coordinate to the N(7) positions of guanosine nucleosides, as revealed by 1H, 31P, and 195Pt NMR spectroscopy. The NMR spectra were selectively broadened owing to distance-dependent relaxation from the unpaired electron localized on the nitroxyl radical of the 4-aminoTEMPO ligand. Platination of d(GpG) by the mixed amine complex 7 afforded two orientational isomers which differed with respect to the positioning of the 4-aminoTEMPO group toward either the 3′ or 5′ side of the phosphodiester linkage. The purified orientational isomers were readily distinguished by selective broadening of the 1H NMR resonances of the 3′ and 5′ deoxyribose rings. The minimum energy solution structure for the 5′ orientational isomer of the platinated dinucleotide cis-[Pt(NH3)(4-aminoTEMPO){d(GpG)}]+ (13) was determined by NMR methods including combined diamagnetic (J coupling constants) and paramagnetic (electron-1H, 31P distances) constraints. Moreover, with the paramagnetic spin probe, we have been able to obtain the first observable NMR distance constraints for determining the configuration of the ζ or α torsion angles in any oligonucleotide. Dynamics trajectories (200 ps) for 13 demonstrated that only computations including paramagnetic distance constraints could determine the ζ-, α- conformation of the phosphodiester linkage and the conformation of the 4-aminoTEMPO ligand. These NMR data and computational methods demonstrate the utility of long-range paramagnetic distance constraints in elucidating the NMR solution structures of DNA modified by cisplatin analogues.
Synthesis, structure, and biological activity of mixed-ligand platinum(II) complexes with aminonitroxides
Sen',Rukina,Tkachev,Pis'menskii,Volkova,Goncharova,Raevskaya,Tikhomirov,Gorbacheva,Konovalova
, p. 1613 - 1619 (2008/10/08)
Mixed-ligand platinum complexes cis-PtII(R6NH2)(NH3)X2 and cis-PtII(R5NH2)(NH3)X2 (R6 is 2,2,6,6-tetramethyl-4-piperidyl-1-oxyl and R5 is 2,2,5,5-tetramethyl-3-pyrrolidinyl-1-oxyl) were synthesized by either the reaction of aminonitroxides RNH2 with Na[PtII(NH3)Cl2I] generated in situ (for X2 = CII) or by replacement of the iodo-chloro ligands in cis-PtII(RNH2)(NH3)CII by dichloro and oxalato ligands. The complexes obtained were characterized by elemental analysis and by IR, UV, and ESR spectra. For cis-PtII(R5NH2)(NH3)Cl2, crystal and molecular structures were determined by X-ray diffraction analysis. Cisplatin accelerates autooxidation of methyl linoleate and the platinum nitroxide complexes synthesized exhibit antioxidant properties. The rate of isolated DNA binding with the new complexes is almost as high as that for cisplatin. cis-Pt11(R6NH2)(NH3)Cl2 exhibits the highest antitumor activity. The high antitumor activity of platinum nitroxide complexes shows that the possible radical component is not a crucial factor in the cytotoxic action of cisplatin.
