TY - JOUR
T1 - Kinetics and mechanism for reduction of oral anticancer platinum(iv) dicarboxylate compounds by L-ascorbate ions
AU - Lemma, Kelemu
AU - Sargeson, Alan M.
AU - Elding, Lars I.
PY - 2000
Y1 - 2000
N2 - Ascorbate(Asc) reductions of the oral anticancer platinum(iv) prodrugs m,trans,cù-[PtCl2(OAc)2(cha)(NH 3)](JM216) and cis, trans;,cis-[PtCl2(OCOC3H7) 2(cha)(NH3)](JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)](JM394) and trans,trans,trans-[PtCI2(OAc)2(cha)(NH 3)](JM576)(OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to rà-[PtCl2(cha)(NH3)](JM118) and JM394 and 576 to CM- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: -d[Pt(iv)]/dt = k [Pt(iv)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2-] + [H2Asc] + [H2Asc]. Reduction of JM216 and JM221 is slow(overall rate constants k298 = 5.08 ±10-2 and 3.25 × 1(T2 mol-1 dm3 s-1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster(k298 = 230 ±6 mol-1 dm3 s-1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2 and less efficiently by H Asc- leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc- and Asc2- at 25 °C are 0.548 ±0.004 and(4.46 ±0.01) × 106 mol-1 dm3 s-1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2- at 25 °C are calculated to be 672 ±15 and 428 ±10 mol1 dm3 s-1, respectively and reduction by HAsc- was not observed under these conditions. Thus, Asc2- is up to 7 orders of magnitude more efficient as a reductant than HAsc-. H2Asc is virtually inactive. The activation parameters Asc2- and AS+ for reduction of JM216, JM221, JM394, and JM576 by Asc2- are 52 ±1,46 ±1, 56.2 ±0.5, and 63 ±2 kJ mol-1 and -97 ±4, -120 ±4, -24 ±2, and -8 ±5 J K-1 mol-1, respectively. An isokinetic relationship gives further support to the mechanistic assignments.
AB - Ascorbate(Asc) reductions of the oral anticancer platinum(iv) prodrugs m,trans,cù-[PtCl2(OAc)2(cha)(NH 3)](JM216) and cis, trans;,cis-[PtCl2(OCOC3H7) 2(cha)(NH3)](JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)](JM394) and trans,trans,trans-[PtCI2(OAc)2(cha)(NH 3)](JM576)(OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to rà-[PtCl2(cha)(NH3)](JM118) and JM394 and 576 to CM- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: -d[Pt(iv)]/dt = k [Pt(iv)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2-] + [H2Asc] + [H2Asc]. Reduction of JM216 and JM221 is slow(overall rate constants k298 = 5.08 ±10-2 and 3.25 × 1(T2 mol-1 dm3 s-1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster(k298 = 230 ±6 mol-1 dm3 s-1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2 and less efficiently by H Asc- leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc- and Asc2- at 25 °C are 0.548 ±0.004 and(4.46 ±0.01) × 106 mol-1 dm3 s-1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2- at 25 °C are calculated to be 672 ±15 and 428 ±10 mol1 dm3 s-1, respectively and reduction by HAsc- was not observed under these conditions. Thus, Asc2- is up to 7 orders of magnitude more efficient as a reductant than HAsc-. H2Asc is virtually inactive. The activation parameters Asc2- and AS+ for reduction of JM216, JM221, JM394, and JM576 by Asc2- are 52 ±1,46 ±1, 56.2 ±0.5, and 63 ±2 kJ mol-1 and -97 ±4, -120 ±4, -24 ±2, and -8 ±5 J K-1 mol-1, respectively. An isokinetic relationship gives further support to the mechanistic assignments.
UR - http://www.scopus.com/inward/record.url?scp=0000886006&partnerID=8YFLogxK
U2 - 10.1039/a909484i
DO - 10.1039/a909484i
M3 - Article
SN - 1470-479X
SP - 1167
EP - 1172
JO - Journal of the Chemical Society. Dalton Transactions
JF - Journal of the Chemical Society. Dalton Transactions
IS - 7
ER -