Synthesis, characterization, and reactivity of platinum cysteinato and related thiolato complexes: model studies of the reversal of cisplatin nephrotoxicity
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1995
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University of Hawaii at Manoa
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Abstract
Reaction of PtCl2(2,2'-bipyridine) (1) with N-acetyl-L-cysteine (L-accysH), mercaptopropanoic acid (mpaH), mercaptoacetic acid (maaH), 2-aminoethanethiol (aetH), L-cysteine (cysH), penicillamine (pen), or penicillamine methyl ester (penOMe) in water at pH 7.0 leads to the isolation of [Pt2(µ-L-S)2(bpy)2] (L = L-accys (2), mpa (3), maa (4), aet (5), cys (6), pen (10), and penOMe (12». The molecular structure of 2 was determined through a single crystal X-ray diffraction study. Crystallographic data for compound 2•4 H20: monoclinic C2, Z =4, a =19.491(4) Å, b =19.266(4) Å, c = 11.494(2) Å, β= 102.88°, V = 4208(2) Å3. The lH and l3C{ IH} NMR spectra of 2-6 in D20 solution are consistent with a µ-S dimeric formulation. The 112-N,S monomeric complexes, Pt(112L- N,S)(bpy) (L =aet (8), cys (9), pen (11» are produced directly from reaction of 1 with aet, cys or pen at pH 11.0, or in the case of 8 and 9, upon adjusting an aqueous solution of 5 and 6 to pH 11. Complexes 8, 9, and 11 were characterized by 1Hand l3C {1H} NMR spectral data. The chemical shifts observed in the 195pt NMR spectroscopic studies of the µ-S dimer complexes 2, and 5 are markedly different from that observed for the 112N, S monomeric complex 8. Heating an aqueous solution of 6 at 700 C results in its conversion to the 112-N,S monomeric complex 9. In contrast, both 5 and 12 are stable at 800 C, thereby suggesting that thermal conversion of 6 to 9 proceeds through deprotonation of the amine via N-O proton transfer. The reactivity of 2 with Sodium diethyldithiocarbamate Na(ddtc), thiourea, KSCN, cys, aet, pen, 2-mercaptopyridine (pyS), 3-hydroxy-2-mercaptopyridine (HOpyS), 2-mercaptopyrimidine (primS), and 4-methyl-2-mercaptopyrimidine (MeprimS) in pH 7.4 buffer was investigated by IH NMR spectroscopy. The reactivity of these ligands towards 2 was effected by both electronic and steric factors. The Pt-S bond of 2 was susceptible to rapid cleavage by Na(ddtc), cys, pyS, and primS within 15 minutes, thus suggesting that these may be effective for reversal of cisplatin-induced nephrotoxicity.
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Cisplatin, Organoplatinum compounds, Toxicological interactions
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Theses for the degree of Doctor of Philosophy (University of Hawaii at Manoa). Chemistry; no. 3270
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