期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 5, 页码 1734-1745出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01253
关键词
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资金
- National University of Singapore Academic Research Fund [R-148-000-153-112, R-148-000-184-112]
- National Medical Research Council Grant [NMRC/NIG/0050/2009]
The dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) enzymes are involved in the process of tumor cell growth and survival. The 4,6-diamino-1,2-dihydro1,3,5-triazine scaffold is well-established as a useful scaffold for DHFR inhibition, while chalcones have been reported to be inhibitors of TrxR. In this study, 15 novel compounds designed by the structural combination of the 4,6-diamino-1,2-dihydro1,3,5-triazine and chalcone scaffolds via a diether linker were successfully synthesized and characterized. All of the compounds demonstrated dual inhibition against DHFR and TrxR when they were assessed by in vitro enzyme assays. The compounds also exhibited antiproliferative activity against the MCF-7 and HCTI16 cells. The more potent analogs 14 and 15 were found to inhibit cellular DHFR and TrxR activities in HCT116 cells. Therefore, this study provided compelling evidence that 14 and 15 could exert their anticancer property via multitarget inhibition at the cellular level.
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