Discovery of the Next-Generation Platinum-Based Anticancer Agents for Combating Oxaliplatin-Induced Drug Resistance

Oxaliplatin-based
chemotherapy has proven to be one of the most
effective treatments for advanced or metastatic colorectal cancer.
However, increasing clinical resistance to oxaliplatin poses unprecedented
challenges for both patients and clinicians. Despite extensive efforts
to combat this issue, to date, no new molecules have been discovered
that can successfully replace oxaliplatin. With the aim of developing
a new generation of Pt(II)-based anticancer agents in response to
the challenges of oxaliplatin-induced drug resistance, we performed
a systematic screening of new Pt(II)-complexes with a quantitative
structure–activity relationship (QSAR) study based on their
antiresistance activity against oxaliplatin-resistant colon cancer
cells. The results revealed that both the structure and chirality
of the chelating ligand had a significant impact on the antiresistance
properties of the Pt(II)-complexes. Our study culminated in the identification
of chiral R-binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates
that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency.