Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted classical antifolates with selective uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis
dc.contributor.author | Xiang, W | |
dc.contributor.author | Dekhne, A | |
dc.contributor.author | Doshi, A | |
dc.contributor.author | O'Connor, C | |
dc.contributor.author | Hou, Z | |
dc.contributor.author | Matherly, LH | |
dc.contributor.author | Gangjee, A | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-01-23T21:18:34Z | |
dc.date.available | 2024-01-23T21:18:34Z | |
dc.date.issued | 2019-12-01 | |
dc.identifier.issn | 0968-0896 | |
dc.identifier.issn | 1464-3391 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/31679978 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/192133 | en |
dc.description.abstract | We previously showed that classical 6-substituted pyrrolo[2,3-d]pyrimidine antifolates bind to folate receptor (FR) α and the target purine biosynthetic enzyme glycinamide ribonucleotide formyltransferase (GARFTase) with different cis and trans conformations. In this study, we designed novel analogs of this series with an amide moiety in the bridge region that can adopt both the cis and trans lowest energy conformations. This provides entropic benefit, by restricting the number of side-chain conformations of the unbound ligand to those most likely to promote binding to FRα and the target enzyme required for antitumor activity. NMR of the most active compound 7 showed both cis and trans amide bridge conformations in ~1:1 ratio. The bridge amide group in the best docked poses of 7 in the crystal structures of FRα and GARFTase adopted both cis and trans conformations, with the lowest energy conformations predicted by Maestro and evidenced by NMR within 1 kcal/mol. Compound 7 showed ~3-fold increased inhibition of FRα-expressing cells over its non-restricted parent analog 1 and was selectively internalized by FRα over the reduced folate carrier (RFC), resulting in significant in vitro antitumor activity toward FRα-expressing KB human tumor cells. Antitumor activity of 7 was abolished by treating cells with adenosine but was incompletely protected by 5-aminoimidazole-4-carboxamide (AICA) at higher drug concentrations, suggesting GARFTase and AICA ribonucleotide formyltransferase (AICARFTase) in de novo purine biosynthesis as the likely intracellular targets. GARFTase inhibition by compound 7 was confirmed by an in situ cell-based activity assay. Our results identify a “first-in-class” classical antifolate with a novel amide linkage between the scaffold and the side chain aryl L-glutamate that affords exclusive selectivity for transport via FRα over RFC and antitumor activity resulting from inhibition of GARFTase and likely AICARFTase. Compound 7 offers significant advantages over clinically used inhibitors of this class that are transported by the ubiquitous RFC, resulting in dose-limiting toxicities. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | Elsevier | |
dc.relation.haspart | 115125 | |
dc.subject | Amide bridge | |
dc.subject | Classical antifolates | |
dc.subject | Folate receptor | |
dc.subject | Pyrrolo[2,3-d]pyrimidines | |
dc.subject | Selective uptake | |
dc.subject | Amides | |
dc.subject | Animals | |
dc.subject | Antineoplastic Agents | |
dc.subject | Biosynthetic Pathways | |
dc.subject | CHO Cells | |
dc.subject | Cell Line, Tumor | |
dc.subject | Cricetulus | |
dc.subject | Folate Receptor 1 | |
dc.subject | Folic Acid Antagonists | |
dc.subject | Humans | |
dc.subject | Models, Molecular | |
dc.subject | Neoplasms | |
dc.subject | Purine Nucleotides | |
dc.subject | Pyridines | |
dc.subject | Pyrroles | |
dc.title | Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted classical antifolates with selective uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis | |
dc.type | Article | |
dc.identifier.pmid | 31679978 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/192133/2/Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted classical antifolates with selective uptake by folate.pdf | |
dc.identifier.doi | 10.1016/j.bmc.2019.115125 | |
dc.identifier.doi | https://dx.doi.org/10.7302/22133 | |
dc.identifier.source | Bioorganic and Medicinal Chemistry | |
dc.description.version | Published version | |
dc.date.updated | 2024-01-23T21:18:31Z | |
dc.identifier.volume | 27 | |
dc.identifier.issue | 23 | |
dc.identifier.startpage | 115125 | |
dc.identifier.name-orcid | Xiang, W | |
dc.identifier.name-orcid | Dekhne, A | |
dc.identifier.name-orcid | Doshi, A | |
dc.identifier.name-orcid | O'Connor, C | |
dc.identifier.name-orcid | Hou, Z | |
dc.identifier.name-orcid | Matherly, LH | |
dc.identifier.name-orcid | Gangjee, A | |
dc.working.doi | 10.7302/22133 | en |
dc.owningcollname | Internal Medicine, Department of |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.