Synthesis and preliminary antiproliferative activity of new pteridin-7(8H)-one derivatives

Eur J Med Chem. 2018 Jan 1:143:1396-1405. doi: 10.1016/j.ejmech.2017.10.037.

Zhong-Hua Li ¹, Tao-Qian Zhao ¹, Xue-Qi Liu ¹, Bing Zhao ¹, Chao Wang ¹, Peng-Fei Geng ¹, Ya-Quan Cao ¹, Dong-Jun Fu ¹, Li-Ping Jiang ², Bin Yu ³, Hong-Min Liu ⁴

Affiliations

1 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China.
2 School of Basic Medical Science, Central South University, Changsha 410013, PR China.
3 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: zzuyubin@hotmail.com.
4 Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, PR China; Key Laboratory of Technology of Drug Preparation (Zhengzhou University), Ministry of Education of China, Zhengzhou 450001, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Zhengzhou 450001, PR China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.

PMID: 29113745 DOI: 10.1016/j.ejmech.2017.10.037

Abstract

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8H)-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC₅₀ values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and Apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of Caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7H-purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established.

Keywords

Antiproliferative activity; Apoptosis; Cell cycle arrest; Pteridin-7(8H)-one.

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