The impact of different chelating leaving groups on the substitution kinetics of mononuclear PtII(1,2-trans-R,R-diaminocyclohexane)(X–Y) complexes

Abstract

A set of three oxaliplatin derivatives containing 1,2-trans-R,R-diaminocyclohexane (dach) as a spectator ligand and different chelating leaving groups X-Y, viz., [Pt(dach)(O,O-cyclobutane-1,1-dicarboxylate)], or Pt(dach)(CBDCA), [Pt(dach)(N,O-glycine)]+, or Pt(dach)(gly), and [Pt(dach)(N,S-methionine)]+, or Pt(dach)(L-Met), where L-Met is L-methionine, were synthesized and the crystal structure of Pt(dach)(gly) was determined by X-ray diffraction. The effect of the leaving group on the reactivity of the resulting Pt(II) complexes was studied for the nucleophiles thiourea, glutathione (GSH) and L-Met under pseudo-first-order conditions as a function of nucleophile concentration and temperature, using UV-vis spectrophotometric techniques. 1H NMR spectroscopy was used to follow the substitution of the leaving group by guanosine 5'-monophosphate (5'-GMP2-) under second-order conditions. The rate constants indicate for all reactions a direct substitution of the X-Y chelate by the selected nucleophiles, thereby showing that the nature of the chelate, viz., O-O (CBDCA2-), N-O (glycine) or S-N (L-Met), respectively, plays an important role in the kinetic and mechanistic behavior of the Pt(II) complex. The k1 values for the reaction with thiourea, L-Met, GSH and 5'-GMP2- were found to be as follows (10(3) k1, 37.5 degrees C, M(-1) s(-1)): Pt(dach)(CBDCA) 61 +/- 2, 21.6 +/- 0.1, 23 +/- 1, 0.352 +/- 0.002; Pt(dach)(gly) 82 +/- 3, 6.2 +/- 0.2, 37 +/- 1, 1.77 +/- 0.01; Pt(dach)(L-Met) (thiourea, GSH) 62 +/- 2, 24 +/- 1. The activation parameters for all reactions studied suggest an associative substitution mechanism.

Characterizing Pt‐Derived Anticancer Drugs from First Principles: The Case of Oxaliplatin in Aqueous Solution

“…Several studies have appeared on the substitution kinetics and chemical stability of oxaliplatin in water solution, [9,10] in NaCl solution, [9] and in the presence of different chemical species (such as chloride anions, [11,12] diethyl dithiocarbamate, [13] carbonate buffers, [14] different nucleophiles, [15,16] etc.). The only structural determination of oxaliplatin in aqueous solution comes from the contributions of Provost and collaborators who have characterized it by means of EXAFS spectroscopy.…”

Novel platinum(II) complexes of long chain aliphatic diamine ligands with oxalato as the leaving group: comparative cytotoxic activity relative to chloride precursors

“…The IC 50 values, calculated from the dose survival curves obtained after 120 h of drug exposure (MTT test), are shown in We observed that, in all cell lines assessed, the cytotoxicity was influenced by the leaving group, with oxalato complexes showing decreased activity compared to chloride precursors. Especially with the B16-F10 cell line, IC 50 values vary from 6.3 to 3.6 µmol L -1 for chloride complexes (1-4) and from 38.0 to 16.6 µmol L -1 for the oxalato analogues (5)(6)(7)(8). With the A 549 cell line, while the IC 50 value for chloride complexes is around 10 µmol L -1 , those for the oxalatos vary from 60.6 to 13.5 µmol L -1 .…”

“…[4][5][6] Carboplatin was designed to overcome the severe side effects of cisplatin, and, indeed, the replacement of the labile chloride ligands by a comparatively more stable bidentate O-O leaving group resulted in a modified pharmacodynamic behavior and a more tolerable toxicological profile. 7 However, the cross-resistance between cisplatin and carboplatin makes them both ineffective in the treatment of patients who fail to respond to therapy.…”

EXAFS Debye-Waller factors issued from Car-Parrinello molecular dynamics: Application to the fit of oxaliplatin and derivatives

“…Its main pharmaceutical interest comes from the diaminocyclohexane ligand, 16 which is generally considered as inert. 17,18 The EX-AFS spectrum of oxaliplatin as well as of several parent drugs and their degradation products have been previously recorded and analyzed by some of our group. 19 In addition, we performed a Car-Parrinello molecular dynamics (CP-MD) simulation of ethyldiamineoxalatoplatinum(II) (EDO-Pt), a model structure for oxaliplatin obtained by removal of the outer part of the cyclohexane ring ( Fig.…”