Tian Chao, Zhang Zhili, Zhou Shouxin, Yuan Mengmeng, Wang Xiaowei, Liu Junyi
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.
Chem Biol Drug Des. 2016 Mar;87(3):444-54. doi: 10.1111/cbdd.12681. Epub 2015 Dec 29.
Based on our previous work, seven N(5) -substituted 8,10-dideazatetrahydrofolate analogues and one 8-deazatetrahydrofolate analogue were designed and synthesized as human dihydrofolate reductase (hDHFR) inhibitors. All compounds were assayed versus DHFR and five different cancer cell lines. The biological assay indicated that replacing N(10) with carbon would significantly increase inhibitory activities against DHFR and cytotoxicities against cancer cell lines. Compound 19a with 4-amino and N(5) -formyl showed great antitumour activities against HL-60, Bel-7402 and BGC823 which were much better than MTX.
基于我们之前的工作，设计并合成了7种N(5)-取代的8,10-二脱氮四氢叶酸类似物和1种8-脱氮四氢叶酸类似物作为人二氢叶酸还原酶（hDHFR）抑制剂。所有化合物均针对DHFR和5种不同的癌细胞系进行了测定。生物学试验表明，用碳取代N(10)会显著提高对DHFR的抑制活性和对癌细胞系的细胞毒性。具有4-氨基和N(5)-甲酰基的化合物19a对HL-60、Bel-7402和BGC823显示出很强的抗肿瘤活性，比甲氨蝶呤（MTX）要好得多。
