title: 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.
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors.forename: Lalit K
authors.initials: LK
authors.lastname: Golani
authors.forename: Christina
authors.initials: C
authors.lastname: George
authors.forename: Sai
authors.initials: S
authors.lastname: Zhao
authors.forename: Sudhir
authors.initials: S
authors.lastname: Raghavan
authors.forename: Steven
authors.initials: S
authors.lastname: Orr
authors.forename: Adrianne
authors.initials: A
authors.lastname: Wallace
authors.forename: Mike R
authors.initials: MR
authors.lastname: Wilson
authors.forename: Zhanjun
authors.initials: Z
authors.lastname: Hou
authors.forename: Larry H
authors.initials: LH
authors.lastname: Matherly
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D058975:Folate Receptor 1 / Q000502:physiology*; D058976:Folate Receptor 2 / Q000502:physiology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D058972:Folic Acid Transporters / Q000502:physiology*; D006801:Humans; D007624:KB Cells; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D058975:Folate Receptor 1; D058976:Folate Receptor 2; D005493:Folic Acid Antagonists; D058972:Folic Acid Transporters; D011743:Pyrimidines