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Synthesis, characterization, and reactivity of platinum cysteinato and related thiolato complexes : model studies of the reversal of cisplatin nephrotoxicity

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Title: Synthesis, characterization, and reactivity of platinum cysteinato and related thiolato complexes : model studies of the reversal of cisplatin nephrotoxicity
Authors: Mitchell, Kathryn Allison
Keywords: Cisplatin
Organoplatinum compounds
Toxicological interactions
Issue Date: 1995
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.
Description: Thesis (Ph. D.)--University of Hawaii at Manoa, 1995.
Includes bibliographical references (leaves 121-123).
xvii, 123 leaves, bound ill. 29 cm
Rights: All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections:Ph.D. - Chemistry

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