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.