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Activation of Platinum(IV) Prodrugs By Motexafin Gadolinium as a Redox Mediator
Author(s) -
Thiabaud Gregory,
McCall Rebecca,
He Guangan,
Arambula Jonathan F.,
Siddik Zahid H.,
Sessler Jonathan L.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201604236
Subject(s) - prodrug , chemistry , oxaliplatin , cytotoxicity , redox , platinum , combinatorial chemistry , gadolinium , nuclear chemistry , stereochemistry , catalysis , biochemistry , in vitro , cancer , organic chemistry , medicine , colorectal cancer
Water‐soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co‐incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt IV to Pt II promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt IV species in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present “activation by reduction” approach may allow for the cancer‐selective enhancement in the cytotoxicity of Pt IV prodrugs.