Syntheses and Antiproliferative Evaluation of 6-Thienyl, 6-Polyphenyl Aryl and 6-Naphthyl Derivatives of 2,4-Diaminopyrido[3,2-d]pyramidine as Non-classical Antifolate Targeting DHFR

doi:10.1007/s40242-017-7153-3

Chemical Research in Chinese Universities ›› 2017, Vol. 33 ›› Issue (4): 559-568.doi: 10.1007/s40242-017-7153-3

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Syntheses and Antiproliferative Evaluation of 6-Thienyl, 6-Polyphenyl Aryl and 6-Naphthyl Derivatives of 2,4-Diaminopyrido[3,2-d]pyramidine as Non-classical Antifolate Targeting DHFR

YANG Jiajia¹, WANG Meng¹, LI Xia³, FAN Ningning¹, XUE Liangmin¹, LI Hao¹, TIAN Chao¹, WANG Xiaowei¹, LIU Junyi^1,2, ZHANG Zhili¹

1. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China;
2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, P. R. China;
3. Marine College, Shandong University, Weihai 264209, P. R. China

Received:2017-04-24 Revised:2017-05-25 Online:2017-08-01 Published:2017-07-19
Contact: ZHANG Zhili E-mail:lilybmu@bjmu.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China（Nos.21172014，21302007）.

Abstract

Abstract:

A series of 6-thienylethenyl, 6-polyphenyl arylethenyl, 6-thienylethyl and 6-polyphenyl arylethyl derivatives of 2,4-diaminopyrido[3,2-d]pyrimidine for targeting dihydrofolate reductase(DHFR) was designed and synthesized as non-classical antifolates in order to overcome drug resistance. The compounds were evaluated for in vitro antitumor activities, rhDHFR and antimicrobial activities. All the compounds exhibited antitumor activities, with values in the range of 0.13-17.8 μmol/L against HL-60, HeLa and A549. Both the types of aryl groups and the orientation of polyphenyl aryl made an impact on the biological activities. 6-Naphthylethyl derivatives 5c and 5d were proved to be the most active DHFR inhibitors, which were more potent than 6-phenylethyl, 6-thienylethyl and 6-biphenylethyl derivatives. Docking studies reveal that flexible saturated carbon-carbon bond of C₉-C₁₀ is essential for biological activities in molecular backbone. Antimicrobial test shows that most of the compounds exhibit antibacterial activities.

Key words: Non-classical antifolate, Dihydrofolate reductase(DHFR), Antitumor, Antimicrobial

YANG Jiajia, WANG Meng, LI Xia, FAN Ningning, XUE Liangmin, LI Hao, TIAN Chao, WANG Xiaowei, LIU Junyi, ZHANG Zhili. Syntheses and Antiproliferative Evaluation of 6-Thienyl, 6-Polyphenyl Aryl and 6-Naphthyl Derivatives of 2,4-Diaminopyrido[3,2-d]pyramidine as Non-classical Antifolate Targeting DHFR[J]. Chemical Research in Chinese Universities, 2017, 33(4): 559-568.

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Syntheses and Antiproliferative Evaluation of 6-Thienyl, 6-Polyphenyl Aryl and 6-Naphthyl Derivatives of 2,4-Diaminopyrido[3,2-d]pyramidine as Non-classical Antifolate Targeting DHFR

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