2. Academic Validation
  3. Development of Integrated Bioorthogonal Self-Catalyzed NO Donor/Platinum(IV) Prodrugs for Synergistical Intervention against Triple-Negative Breast Cancer

Development of Integrated Bioorthogonal Self-Catalyzed NO Donor/Platinum(IV) Prodrugs for Synergistical Intervention against Triple-Negative Breast Cancer

  • J Med Chem. 2023 Dec 18. doi: 10.1021/acs.jmedchem.3c01693.
Chen Zhang 1,  Jie Zhu 1,  Xun Yuan 1,  Zhengsheng Yan 1,  Hui Ye 1,  Tao Xiong 1,  Anning Xu 1,  Cunrui Li 1,  Duorui Ji 1,  Shan Yang 2,  Juan Zhang 3,  Yihua Zhang 1,  Jianbing Wu 1,  Zhangjian Huang 1 4
Affiliations

Affiliations

  • 1 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, P. R. China.
  • 2 Xinjiang Key Laboratory of Neurological Disorder Research, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi 830028, P. R. China.
  • 3 School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, P. R. China.
  • 4 School of Pharmacy, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi 830054, P. R. China.
PMID: 38110353 DOI: 10.1021/acs.jmedchem.3c01693
Abstract

The platinum(IV) prodrug strategy is attractive for the synergistic antitumor effect. High levels (>400 nM) of nitric oxide (NO) exert promising Cancer inhibition effects via multiple mechanisms. Herein, we designed and synthesized a new group of integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs bearing long alkyl chains to enhance the stability in circulation, while the cytoplasmic reductants trigger cascade activation to release Pt and NO in tumor cells. Specifically, compound 10c exhibited an improved stability, favorable pharmacokinetic properties (AUC(0-t) of 2210.10 h*ng/mL), potent anti-triple-negative breast Cancer (TNBC) effects (71.08% tumor growth inhibition (TGI) against the MDA-MB-231 xenograft model), potent in vivo anti-TNBC lung metastasis activity, and acceptable low toxicity. Importantly, NO released from 10c leads to the S-nitrosation of metal transporters Atox1&ATP7a in TNBC cells, which increases the Pt retention and inhibits lysyl oxidase, generating synergistic tumoricidal and antimetastatic activity. These results may inspire further study on the synergistical therapy of Pt and NO for the treatment of TNBC.

Figures
Products