Novel 8-deaza-5,6,7,8-tetrahydroaminopterin derivatives as dihydrofolate inhibitor: Design, synthesis and antifolate activity

Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
European Journal of Medicinal Chemistry (Impact Factor: 3.45). 06/2008; 44(2):764-71. DOI: 10.1016/j.ejmech.2008.04.017
Source: PubMed


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.

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