DESIGN OF DUAL-TARGET INHIBITORS OF DIHYDROFOLATE REDUCTASE AND THIOREDOXIN REDUCTASE AS ANTICANCER AGENTS

Abstract

THE DIHYDROFOLATE REDUCTASE (DHFR) AND THIOREDOXIN REDUCTASE (TRXR) ENZYMES ARE INVOLVED IN THE PROCESS OF CANCER CELL GROWTH AND SURVIVAL. INHIBITION OF THESE ENZYMES CAN THEREFORE RESULT IN ANTIPROLIFERATIVE ACTIVITY ON CANCER CELLS. 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.

USING THE MTT ASSAY, WE FOUND THAT SOME COMBINATIONS OF 4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINES AND CHALCONES AT A 1:1 MOLAR RATIO DEMONSTRATED SYNERGISTIC ANTIPROLIFERATIVE ACTIVITIES ON THE HCT116 AND MCF-7 CANCER CELL LINES. BASED ON THIS RESULT, WE SYNTHESIZED TWENTY NOVEL COMPOUNDS CONTAINING BOTH THE 4,6-DIAMINO-1,2-DIHYDRO-1,3,5-TRIAZINE SCAFFOLD AND THE CHALCONE MOIETY. MANY OF THE COMPOUNDS DEMONSTRATED GOOD ANTIPROLIFERATIVE ACTIVITY AGAINST MCF-7 AND HCT116. IN VITRO ENZYME ASSAYS SHOWED THAT THE COMPOUNDS INHIBITED RECOMBINANT HUMAN DHFR AND RAT LIVER TRXR. CELL-BASE