2. Academic Validation
  3. Design, Synthesis, and Anti-Cancer Evaluation of Novel Cyclic Phosphate Prodrug of Gemcitabine

Design, Synthesis, and Anti-Cancer Evaluation of Novel Cyclic Phosphate Prodrug of Gemcitabine

  • J Med Chem. 2023 Mar 23;66(6):4150-4166. doi: 10.1021/acs.jmedchem.3c00006.
Liang Zhang 1 2,  Kangjing Qi 1,  Jie Xu 3 4,  Yan Xing 5,  Xuejian Wang 6,  Ling Tong 3,  Zengguo He 1,  Wenfang Xu 5,  Xiaoyang Li 1 2 5,  Yuqi Jiang 1 2 5
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
  • 2 Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, P.R. China.
  • 3 Oncology and Immunology Unit, Research Service Division, WuXi AppTec, Nantong 226299, China.
  • 4 School of Computer Science and Engineering, Central South University, Changsha 410083, China.
  • 5 Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong 266071, P.R. China.
  • 6 College of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
PMID: 36867101 DOI: 10.1021/acs.jmedchem.3c00006
Abstract

ProTide and cyclic phosphate ester are two successful prodrug technologies to overcome the limitations of nucleoside drugs, among which the cyclic phosphate ester strategy has not been widely used in the optimization of gemcitabine. Herein, we designed a series of novel ProTide and cyclic phosphate ester prodrugs of gemcitabine. Cyclic phosphate ester derivative 18c exhibits much higher anti-proliferative activity than positive control NUC-1031 with IC50s of 3.6-19.2 nM on multiple Cancer cells. The metabolic pathway of 18c demonstrates that 18c's bioactive metabolites prolong its anti-tumor activity. More importantly, we separated the two P chiral diastereomers of gemcitabine cyclic phosphate ester prodrugs for the first time, revealing their similar cytotoxic potency and metabolic profile. 18c displays significant in vivo anti-tumor activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results suggest that compound 18c is a promising anti-tumor candidate for treating human castration-resistant prostate and pancreatic Cancer.

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