title: 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor α and the Proton-Coupled Folate Transporter in Human Tumors.
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.
authors: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors: Lei
authors: L
authors: Wang
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
authors: Adrianne
authors: A
authors: Wallace
authors: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors: Sudhir
authors: S
authors: Raghavan
authors: Department of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
authors: Siobhan M
authors: SM
authors: Deis
authors: Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Mike R
authors: MR
authors: Wilson
authors: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors: Si
authors: S
authors: Yang
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.|Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Lisa
authors: L
authors: Polin
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.|Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Kathryn
authors: K
authors: White
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.|Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Juiwanna
authors: J
authors: Kushner
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
authors: Steven
authors: S
authors: Orr
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
authors: Christina
authors: C
authors: George
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
authors: Carrie
authors: C
authors: O'Connor
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.|Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Zhanjun
authors: Z
authors: Hou
authors: Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Shermaine
authors: S
authors: Mitchell-Ryan
authors: Department of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
authors: Charles E
authors: CE
authors: Dann
authors: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.|Department of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.|Department of Pharmacology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
authors: Larry H
authors: LH
authors: Matherly
authors: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
authors: Aleem
authors: A
authors: Gangjee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001692:Biological Transport; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D064593:Heterografts; D006801:Humans; D016513:Mice, SCID; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D000068437:Pemetrexed / Q000494:pharmacology; D051026:Phosphoribosylglycinamide Formyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry; D058979:Proton-Coupled Folate Transporter / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D058975:Folate Receptor 1; D005493:Folic Acid Antagonists; D058979:Proton-Coupled Folate Transporter; D011743:Pyrimidines; D011758:Pyrroles; D013876:Thiophenes; D000068437:Pemetrexed; D051026:Phosphoribosylglycinamide Formyltransferase