Antiproliferative effect, cell cycle arrest and apoptosis generation of novel 6-substituted N-5-formyltetrahydropyrido[3,2-d]pyrimidine derivatives

Abstract

Based on our previous work, a novel series of 6-substituted tetrahydropyrido[3,2-d]pyrimidinesc (6a-6k) bearing formyl group at N-5-position were designed and synthesized. Most compounds were tested for their in vitro antitumor activity against five human cancer cell lines using methotrexate as a positive control. In preliminary antiproliferation assay, some compounds demonstrated micromolar inhibitory effects against all tumor cells. 6-(3,4,5-trimethoxyphenethyl)-5-formyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2,4-diamine (6k) exhibited better antiproliferative activities with IC50 values of 16.6 and 8.5 mu M toward HL-60 and HeLa cells respectively. Furthermore, the inhibition rate of dihydrofolate reductase was over 50% with 6-(3,4,5-trimethoxyphenethyl)-5-formyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine-2,4-diamine (6k) at 20 mu M. Then it was selected for further study regarding their effects on cell cycle analysis, apoptosis assay, the expression of caspase 3/8/9, cleaved-PARP, CDK2 and Cyclin E. We found that the compound induces cell cycle arrest at the S phase, which causes apoptosis.