Abstract
Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Female
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Folate Receptor 1 / metabolism*
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Folic Acid Antagonists / chemical synthesis
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Folic Acid Antagonists / chemistry*
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Folic Acid Antagonists / pharmacology
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Heterografts
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Humans
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Mice, SCID
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Molecular Docking Simulation
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Neoplasm Transplantation
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Phosphoribosylglycinamide Formyltransferase / antagonists & inhibitors
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Proton-Coupled Folate Transporter / metabolism*
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Purine Nucleotides / antagonists & inhibitors*
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Purine Nucleotides / biosynthesis
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis
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Pyrroles / chemistry*
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Pyrroles / pharmacology
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Folate Receptor 1
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Folic Acid Antagonists
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Proton-Coupled Folate Transporter
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Purine Nucleotides
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Pyrimidines
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Pyrroles
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Phosphoribosylglycinamide Formyltransferase