| 内容提要: |
As the third-generation platinum antitumor drug, oxaliplatin structurally
differs from cisplatin and carboplatin by having 1,2-diaminocyclohexane
(DACH) as platinum chelating ligand. Recent studies have demonstrated that the
cellular uptake and the drug-induced neurotoxicity of oxaliplatin are mediated
by certain type of transporters such as organic cation transporters (OCTs), which
are ubiquitously expressed in normal cells and neuron system [1-2].To develop a
new class of platinum complexes as potential targeted therapy drug candidates,
our principal interest is to focus on platinum-glycoconjugates to leverage the
Warburg effect, which is a cellular phenomenon in cancer cells of displaying
high rates of aerobic glycolysis with overexpression of glucose transporters [3].
Sugar conjugation approach has been initiated by Yano and co-workers to
generate novel cisplatin derivatives (L2PtCl2 type platinum(II) complexes) by
using sugar conjugated metal-chelating ligands [4]. In 2013, we reported the first
example for glucose conjugated oxaliplatin type platinum(II) glycoconjugates by
introducing glucose moiety into the malonato leaving group [5].
Our design concept is to take the advantage of the clinical drug oxaliplatin by
retaining the DACH chelating ligand, which plays an important role in
circumventing cross-resistance between cisplatin/carboplatin and oxaliplatin.
Attachment of the sugar moiety with the so called “leaving ligand” such as
malonato or other prototypes of platinum(II) reacting ligands can be expected to
enhance water solubility and at the same time introduce the potential that the
whole complex might be recognized by glucose transporters to target the
Warburg effect. |