Synthesis and antiproliferative activity of a series of novel 6-substituted pyrido[3,2-d]pyrimidines as potential nonclassical lipophilic antifolates targeting dihydrofolate reductase.
Dihydrofolate reductase (DHFR) has been a well-recognized target for the treatment of many diseases. Based on 8,10-dideazaminopterins, which are classical antifolates that potently inhibit DHFR, we have designed a series of novel 2,4-diamino-6-substituted pyrido[3,2-d]pyrimidines. By removing the glutamate moiety and introducing lipophilic groups, we hoped to improve passive diffuse through the cell membranes. The target compounds were efficiently synthesized using one-pot procedure and evaluated in vitro for DHFR inhibition and antitumor activity. Compounds 5e, 5h, 5i and 5k were the most potent inhibitors of recombinant human DHFR (rhDHFR) with IC50values in the range 0.2-1.0 μM. Analysis using flow cytometric indicated that the effect of compound 5k on cell cycle progression was linked to induction of S phase arrest. Compounds 5g, 5h, 5i and 5k showed broad spectrum antitumor activity against four different tumor cell lines, with IC50values in the range 0.07-23 μM. Molecular docking investigations showed that the trimethoyphenyl ring of compound 5k occupied a position near the cofactor-binding site in the rhDHFR-inhibitor complex, with close intermolecular contacts with Asp21, Phe31, Ser59, Ile60 and Pro61.
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Meng
M
Wang
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Jiajia
J
Yang
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Mengmeng
M
Yuan
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Liangmin
L
Xue
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Hao
H
Li
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Chao
C
Tian
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Xiaowei
X
Wang
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. Electronic address: lilybmu@bjmu.edu.cn.
Junyi
J
Liu
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Zhili
Z
Zhang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D003959:Diamines / Q000138:chemical synthesis / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014407:Tumor Cells, Cultured
C000616871:2,4-diamino-6-(3-methoxylstyryl)pyrido(3,2-d)pyrimidine; C000616872:2,4-diamino-6-(4-fluorostyryl)pyrido(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D003959:Diamines; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase
Anticancer; Antifolate; Dihydrofolate reductase inhibitor; Pyrido[3,2-d]pyrimidines