Design, Synthesis, and Biological Evaluation of Coupled Bioactive Scaffolds as Potential Anticancer Agents for Dual Targeting of Dihydrofolate Reductase and Thioredoxin Reductase.
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-dihydro-1,3,5-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-dihydro-1,3,5-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 HCT116 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.
Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, 117543, Singapore.
Hui-Li
HL
Ng
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei 430030, China.
Xiang
X
Ma
Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, 117543, Singapore.
Eng-Hui
EH
Chew
Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, 117543, Singapore.
Wai-Keung
0000-0003-2568-6021
WK
Chui
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D013762:Tetrahydrofolate Dehydrogenase; D013880:Thioredoxin-Disulfide Reductase