Abstract
2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) α or β (IC50s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC50 < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FRα and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FRα and β over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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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Biological Transport
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CHO Cells
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Cell Line, Tumor
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Cricetulus
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Crystallography, X-Ray
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Female
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Folate Receptor 1 / antagonists & inhibitors*
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Folate Receptor 1 / chemistry
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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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Models, Molecular
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Neoplasm Transplantation
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Pemetrexed / pharmacology
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Phosphoribosylglycinamide Formyltransferase / antagonists & inhibitors
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Phosphoribosylglycinamide Formyltransferase / chemistry
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Proton-Coupled Folate Transporter / antagonists & inhibitors*
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Proton-Coupled Folate Transporter / chemistry
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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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Stereoisomerism
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry*
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Thiophenes / pharmacology
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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Pyrimidines
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Pyrroles
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Thiophenes
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Pemetrexed
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Phosphoribosylglycinamide Formyltransferase