~(195)Pt NMR-FOURIER SPECTROSCOPY IN THE ANALYSIS OF THE MECHANISM OF THE CYTOSTATIC ACTIVITY OF PLATINUM COMPLEXES

摘要

Interaction of platinum complexes with two model targets (polynucleotides of different length and GTP-tubulin) was analyzed by means of ~(195)Pt NMR-Fourier spectroscopy. Slow hydrolysis of cis-dichlorodiamineplatinum (complexⅠ) is followed by rapid binding of the released aqua-form cis-[Pt(NH_3)_2ClH_2O]~+ (complex Ⅱ) with polynucleotides, two signals being recorded at δ = -1841 and -2304 ppm. Unlike the aqua-form, the monohydroxo-form, cis -[Pt(NH_3)_2OHCH (complex Ⅲ ), interacts with polynucleotides very slowly. The signal at δ = -2304 ppm is shifted downfield (δ = -2450 ppm). An agreement between the resonance at δ = -2450 ppm and that of the tetracoordinated complex of Pt(Ⅱ) is supported by the resonance of cis-[Pt(NH_3)_4]`(2=) in the same spectral region (δ = -2470 ppm). Cyclization of monofunctional adducts of cis-[Pt(NH_3)_2(N)Cl]~+ (Ⅳ) into bifunctional adducts is slower than monofunctional binding of the aqua-form (Ⅱ). Removing cloride ligands with AgNO_3 yields cis-[Pt(NH_3),(N)H_2O]~(2+) (complex V), which immediately forms a chelate giving rise to a resonance at δ = -2450 ppm. ~(195)Pt NMR-Fourier spectroscopy analysis of interaction of cis-dichlorodiamineplatinum with tubulin bound GTP showed that originally observed resonance in NMR ~(195)Pt spectra at ―2060ppm decreases giving rise to a resonance at ―2030ppm, which corresponds to the bidentate coordination of the platinum complex. Mechanisms of action of platinum complexes on the intercellular molecular targets and nature of cytostatic effects of platinum are discussed on the basis of the obtained ~(195)Ft NMR -spectroscopy data.