Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: design, synthesis and antifolate activity.
We report, for the first time, the synthesis and biological activities of 8-deaza-5,6,7,8-tetrahydroaminopterin 9, and the 5-substituted and 5,10-disubstituted analogues 11, 13, 15, and 17. The analogues were obtained from key compound diethyl 8-deaza-5,6,7,8-tetrahydroaminopterin 8 following the catalytic reduction of the pyridine ring of diethyl 8-deaza aminopterin 5. The five novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives were assayed in vitro for their cytotoxicity on BGC-823, HL-60, Bel-7402 and Hela tumor cell lines, and inhibition on recombinant human dihydrofolate reductase (DHFR), among which the most potent molecule (compound 9) was about 4- to 10-fold poorer than MTX on the four kinds of tumor cell lines, and its effect on DHFR was about 17-fold poorer than MTX. The docking studies were followed to explain the biological testing results.
Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
Zhili
Z
Zhang
Jun
J
Wu
Fuxiang
F
Ran
Ying
Y
Guo
Ran
R
Tian
Shouxin
S
Zhou
Xiaowei
X
Wang
Zhenming
Z
Liu
Liangren
L
Zhang
Jingrong
J
Cui
Junyi
J
Liu
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D000630:Aminopterin