关键词: 二氢叶酸还原酶抑制剂, 抗肿瘤活性, 合成

In order to obtain antitumor candidates with potent activity, two novel analogues of dihydrofolate reductase (DHFR) inhibitors 3c and 4b were designed and synthesized. The synthetic routes were as follows: 1c was synthesized using chloroacetonitrile, carboxylate and 2,4,6-triamino-pyrimidine as raw materials by condensation, cyclization and reduction. 2d was synthesized using 2-thiophene formaldehyde and glutamate as raw materials by nitrification, oxidation, condensation and reduction. Then target product 3c was synthesized using 1c and 2d as raw materials by reductive amination and hydrolysis. Target product 4b was synthesized using 1c and 2d as raw materials by 2 steps of reductive amination and hydrolysis. The structures of target products were confirmed by the way of ¹H NMR, ¹³C NMR and MS. The in vitro antitumor activities of target products were evaluated by MTT method. The results showed that 3c exhibited stronger antitumor activity against screened five tumor cell lines (CCRF-CEM, L1210, A549, SGC-7901 and Hep-G2) than the positive control lometrexol, methotrexate and pemetrexed. 3c exhibited stronger antitumor activity against Hep-G2 than the positive control lometrexol, methotrexate and pemetrexed. In addition, 3c and 4b showed much weaker antiproliferative activity toward normal cell SMC than the positive control methotrexate and pemetrexed. This research could provide a theoretical basis for the development of new antitumor drugs.

Key words: DHFR inhibitor, antitumor bioactivity, synthesis