Abstract |
Structure-activity relationships for cellular uptake and inhibition of cell proliferation were studied for 2-amino-4-oxo-6-substituted pyrrolo[2,3-d] pyrimidine thienoyl antifolates in which the terminal l-glutamate of the parent structure (7) was replaced by natural or unnatural amino acids. Compounds 7 and 10-13 were selectively inhibitory toward folate receptor (FR) α-expressing Chinese hamster ovary (CHO) cells. Antiproliferative effects of compounds 7 and 9-13 toward FRα- and FRβ-expressing CHO cells were only partly reflected in binding affinities to FRα and FRβ or in the docking scores with molecular models of FRα and FRβ. Compounds 7 and 11 were potent inhibitors of glycinamide ribonucleotide formyltransferase in de novo purine biosynthesis in KB human tumor cells. These studies establish for the first time the importance of the α- and γ- carboxylic acid groups, the length of the amino acid, and the conformation of the side chain for transporter binding and biological activity of 6-substituted pyrrolo[2,3-d] pyrimidine thienoyl antifolates.
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Authors | Lalit K Golani, Christina George, Sai Zhao, Sudhir Raghavan, Steven Orr, Adrianne Wallace, Mike R Wilson, Zhanjun Hou, Larry H Matherly, Aleem Gangjee |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 57
Issue 19
Pg. 8152-66
(Oct 09 2014)
ISSN: 1520-4804 [Electronic] United States |
PMID | 25234128
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Folate Receptor 1
- Folate Receptor 2
- Folic Acid Antagonists
- Folic Acid Transporters
- Pyrimidines
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Topics |
- Animals
- CHO Cells
- Cricetinae
- Cricetulus
- Folate Receptor 1
(physiology)
- Folate Receptor 2
(physiology)
- Folic Acid Antagonists
(chemical synthesis, pharmacology)
- Folic Acid Transporters
(physiology)
- Humans
- KB Cells
- Models, Molecular
- Pyrimidines
(chemical synthesis, pharmacology)
- Structure-Activity Relationship
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