Abstract
We previously reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a three- (3a) and four-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells. While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and l-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5, and 6) substitutions on the thienoyl ring and with acetylenic insertions in the four-atom bridge were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRα and PCFT over RFC.
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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Alkynes / chemistry
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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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CHO Cells
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Cell Line, Tumor
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Cricetinae
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Cricetulus
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Drug Screening Assays, Antitumor
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Folate Receptor 1 / metabolism*
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Humans
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Proton-Coupled Folate Transporter / metabolism*
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Purines / antagonists & inhibitors*
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Purines / 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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Reduced Folate Carrier Protein / metabolism*
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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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Alkynes
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Antineoplastic Agents
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Folate Receptor 1
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Proton-Coupled Folate Transporter
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Purines
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Pyrimidines
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Pyrroles
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Reduced Folate Carrier Protein
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Thiophenes
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purine