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

• Published in: Journal of medicinal chemistry Vol. 67; no. 12; pp. 10190 - 10210
• Main Authors: Sun, Ziru, Han, Jianbin, Xu, Jun, Song, Weijie, Cui, Yujun, Liu, Yang, Yang, Liu, Meng, Xiaoqi, Huang, Jie, Gao, Qingzhi, Liu, Shengnan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.06.2024; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Chemistry, Medicinal; Drug Discovery; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Mice; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Oxaliplatin - pharmacology; Pharmacology & Pharmacy; Quantitative Structure-Activity Relationship; Science & Technology; CANCER-CELLS; IN-VITRO; CISPLATIN; DNA; GLUCOSE; COMPLEXES; GAMMA-H2AX; PHASE-II; COMBINATION; MOLECULAR-MECHANISMS
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00366

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.