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Structure-activity profiles of novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates with modified amino acids for cellular uptake by folate receptors α and β and the proton-coupled folate transporter.

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.
AuthorsLalit K Golani, Christina George, Sai Zhao, Sudhir Raghavan, Steven Orr, Adrianne Wallace, Mike R Wilson, Zhanjun Hou, Larry H Matherly, Aleem Gangjee
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 19 Pg. 8152-66 (Oct 09 2014) ISSN: 1520-4804 [Electronic] United States
PMID25234128 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Folate Receptor 1
  • Folate Receptor 2
  • Folic Acid Antagonists
  • Folic Acid Transporters
  • Pyrimidines
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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