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: Lei Wang, Adrianne Wallace, Sudhir Raghavan, Siobhan M Deis, Mike R Wilson, Si Yang, Lisa Polin, Kathryn White, Juiwanna Kushner, Steven Orr, Christina George, Carrie O'Connor, Zhanjun Hou, Shermaine Mitchell-Ryan, Charles E Dann 3rd, Larry H Matherly, Aleem Gangjee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 17 Pg. 6938-59 (Sep 10 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26317331 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Folate Receptor 1
• Folic Acid Antagonists
• Proton-Coupled Folate Transporter
• Pyrimidines
• Pyrroles
• Thiophenes
• Pemetrexed
• Phosphoribosylglycinamide Formyltransferase

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biological Transport
• CHO Cells
• Cell Line, Tumor
• Cricetulus
• Crystallography, X-Ray
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Female
• Folate Receptor 1 (antagonists & inhibitors, chemistry)
• Folic Acid Antagonists (chemical synthesis, chemistry, pharmacology)
• Heterografts
• Humans
• Mice, SCID
• Models, Molecular
• Neoplasm Transplantation
• Pemetrexed (pharmacology)
• Phosphoribosylglycinamide Formyltransferase (antagonists & inhibitors, chemistry)
• Proton-Coupled Folate Transporter (antagonists & inhibitors, chemistry)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Pyrroles (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Thiophenes (chemical synthesis, chemistry, pharmacology)