title: Applying the designed multiple ligands approach to inhibit dihydrofolate reductase and thioredoxin reductase for anti-proliferative activity.
abstract: The development of multi-targeting drugs is currently being explored as an attractive alternative to combination therapy, especially for the treatment of complex diseases such as cancer. Dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) are enzymes belonging to two unrelated cellular pathways that are known to contribute towards cancer cell growth and survival. In order to evaluate whether simultaneous inhibition of DHFR and TrxR by dihydrotriazines (DHFR-targeting) and chalcones (TrxR-targeting) may be beneficial, breast MCF-7 and colorectal HCT116 carcinoma cells were treated with combinations of selected dihydrotriazines and chalcones at a 1:1 M ratio. Two combinations demonstrated synergy at low-to-moderate concentrations. Based on this result, four merged dihydrotriazine-chalcone compounds were designed and synthesized. Two compounds, 11a [DHFR IC50 = 56.4 μM, TrxR IC50 (60 min) = 12.6 μM] and 11b [DHFR IC50 = 2.4 μM, TrxR IC50 (60 min) = 10.1 μM], demonstrated in vitro inhibition of DHFR and TrxR. The compounds showed growth inhibitory activity against MCF-7 and HCT116 cells, but lacked cytotoxicity. Molecular docking experiments showed 11b to possess rational binding modes to both the enzymes. In conclusion, this study has not only identified the dihydrotriazine and chalcone scaffolds as good starting points for the development of dual inhibitors of DHFR and TrxR, but also demonstrated the synthetic feasibility of producing a chemical entity that could result in simultaneous inhibition of DHFR and TrxR. Future efforts to improve the antiproliferative profiles of such compounds will look at alternative ways of integrating the two pharmacophoric scaffolds.
authors.affiliation: Department of Pharmacy, Faculty of Science, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
authors.forename: Hui-Li
authors.initials: HL
authors.lastname: Ng
authors.affiliation: Department of Pharmacy, Faculty of Science, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
authors.forename: Shangying
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Faculty of Science, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Chew
authors.affiliation: Department of Pharmacy, Faculty of Science, 18 Science Drive 4, National University of Singapore, 117543, Singapore. Electronic address: phacwk@nus.edu.sg.
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D008024:Ligands; D014227:Triazines; D013762:Tetrahydrofolate Dehydrogenase; D013880:Thioredoxin-Disulfide Reductase
keywords: Antiproliferative activity; Chalcones; Dihydrofolate reductase; Dihydrotriazines; Thioredoxin reductase