Rational synthesis and evaluation of 2,4-diamino-thieno[2,3-d]pyrimidines as antitumor agents

Abstract

Based on structure-guided of thieno[2,3-d]pyrimidine skelecton functionalities and computer-aided drug development strategy, a series of novel 2,4-diamino-thieno[2,3-d]pyrimidine derivatives were designed and synthesized, and their structure confirmed by 1H NMR, 13C NMR and HR-MS. All synthesized compounds were evaluated for antitumor activities against hepatic carcinoma (HepG2) cell lines in vitro, and results showed that all the target compounds exhibited potent antitumor activity. Preliminary comparison indicated that a more bulky substituent group at the C-4 position, and at the same time the introduction of 3-Cl on the phenyl ring with 4-methyl group on the C-2 position of thieno[2,3-d]pyrimidine have remarkable influence on activity. One of the expected target compound 5i showed the best inhibition activities against HepG2 with IC50 value 0.17 μmol/L. To further investigate the structure-activity relationship, the docking experiment of 5i, 5j, 5o and Gefitinib on EGFR were performed. The docking results displayed that compound 5i was able to be tightly embedded in the active pocket of EGFR and the binding energy is most negative with EGFR, which demonstrating that compound 5i can be take a potential lead compound for further lucubrate.