Design, synthesis and biological evaluation of nitric oxide-releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives

Lingling Chi; Hao Wang; Fuqiang Yu; Chao Gao; Honglin Dai; Xiaojie Si; Yuze Dong; Hongmin Liu; Qiurong Zhang

doi:10.1016/j.bmcl.2023.129389

Design, synthesis and biological evaluation of nitric oxide-releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives

Bioorg Med Chem Lett. 2023 Aug 15:92:129389. doi: 10.1016/j.bmcl.2023.129389. Epub 2023 Jun 26.

Authors

Lingling Chi¹, Hao Wang¹, Fuqiang Yu¹, Chao Gao¹, Honglin Dai¹, Xiaojie Si¹, Yuze Dong², Hongmin Liu³, Qiurong Zhang⁴

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China.
² Institute of Drug Discovery and Development, Zhengzhou 450001, China; Center for Drug Safety Evaluation and Research, Zhengzhou 450001, China. Electronic address: dongyuze@zzu.edu.cn.
³ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China; Center for Drug Safety Evaluation and Research, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450052, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001, China. Electronic address: liuhm@zzu.edu.cn.
⁴ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Institute of Drug Discovery and Development, Zhengzhou 450001, China; Center for Drug Safety Evaluation and Research, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou 450052, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou 450001, China. Electronic address: zqr409@yeah.net.

PMID: 37379957
DOI: 10.1016/j.bmcl.2023.129389

Abstract

In this study, a series of nitric oxide (NO) -releasing 5-cyano-6-phenyl-2, 4-disubstituted pyrimidine derivatives were designed and synthesized. In the in vitro biological evaluation, compound 24l exhibited optimal antiproliferative activity against MGC-803 cells with the IC₅₀ value of 0.95 µM, significantly better than that of the positive control 5-FU. In addition, preliminary mechanistic studies indicated that 24l inhibited colony formation and blocked MGC-803 cells in the G0/G1 phase. DAPI staining, reactive oxygen species and apoptosis assays demonstrated that 24l induced apoptosis of MGC-803 cells. Particularly, the most potent compound 24l produced the highest level of NO, and the antiproliferative activity was significantly reduced after preincubation with NO scavengers. In conclusion, compound 24l may be considered as a potential candidate antitumor agent.

Keywords: Antiproliferative activity; Cyanopyrimidine derivatives; MGC-803 cell; Nitric oxide release; Phenylsulfonylfuroxan.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Molecular Structure
Nitric Oxide* / pharmacology
Pyrimidines / pharmacology
Structure-Activity Relationship

Substances

Nitric Oxide
Antineoplastic Agents
Pyrimidines