Abstract
Cobalamin-dependent methionine synthase (MetH) is involved in the process of tumor cell growth and survival. In this study, a novel series of N5-electrophilic substituted tetrahydropteroate analogs without glutamate residue were designed as non-classical antifolates and evaluated for their inhibitory activities against MetH. In addition, the cytotoxicity of target compounds was evaluated in human tumor cell lines. With N5-chloracetyl as the optimum group, further structure research on the benzene substituent and on the 2,4-diamino group was also performed. Compound 6c, with IC50 value of 12.1 μM against MetH and 0.16-6.12 μM against five cancer cells, acted as competitive inhibitor of MetH. Flow cytometry studies indicated that compound 6c arrested HL-60 cells in the G1-phase and then inducted late apoptosis. The molecular docking further explained the structure-activity relationship.
Keywords:
Anticancer; Antifolate; Inhibitor; Methionine synthase; Pyrido[3,2-d]pyrimidine.
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
MeSH terms
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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / antagonists & inhibitors*
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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / chemistry
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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Catalytic Domain
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Cell Line, Tumor
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology*
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / metabolism
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Folic Acid Antagonists / pharmacology*
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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Protein Binding
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Pterins / chemical synthesis
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Pterins / metabolism
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Pterins / pharmacology*
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Folic Acid Antagonists
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Pterins
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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
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MTR protein, human