Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier

DOI

10.1016/j.bmc.2020.115544

Authors

Lalit K. Golani, Duquesne University
Farhana Islam, Duquesne University
Carrie O'Connor, Wayne State University School of Medicine
Aamod S. Dekhne, Wayne State University School of Medicine
Zhanjun Hou, Wayne State University School of Medicine
Larry H. Matherly, Wayne State University School of Medicine
Aleem Gangjee, Duquesne University

Document Type

Journal Article

Publication Date

6-15-2020

Publication Title

Bioorganic and Medicinal Chemistry

Volume

28

Issue

12

ISSN

9680896

Keywords

Folate receptor, Heteroatom bridge, Pyrrolo[2, 3-d]pyrimidine, Reduced folate carrier, Selective uptake

Abstract

Tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine benzoyl compounds based on 2 were isosterically modified at the 4-carbon bridge by replacing the vicinal (C11) carbon by heteroatoms N (4), O (5) or S (6), or with an N-substituted formyl (7), trifluoroacetyl (8) or acetyl (9). Replacement with sulfur (6) afforded the most potent KB tumor cell inhibitor, ~6-fold better than the parent 2. In addition, 6 retained tumor transport selectivity via folate receptor (FR) ? and -? over the ubiquitous reduced folate carrier (RFC). FR?-mediated cell inhibition for 6 was generally equivalent to 2, while the FR?-mediated activity was improved by 16-fold over 2. N (4) and O (5) substitutions afforded similar tumor cell inhibitions as 2, with selectivity for FR? and -? over RFC. The N-substituted analogs 7–9 also preserved transport selectivity for FR? and -? over RFC. For FR?-expressing CHO cells, potencies were in the order of 8 > 7 > 9. Whereas 8 and 9 showed similar results with FR?-expressing CHO cells, 7 was ~16-fold more active than 2. By nucleoside rescue experiments, all the compounds inhibited de novo purine biosynthesis, likely at the step catalyzed by glycinamide ribonucleotide formyltransferase. Thus, heteroatom replacements of the CH2 in the bridge of 2 afford analogs with increased tumor cell inhibition that could provide advantages over 2, as well as tumor transport selectivity over clinically used antifolates including methotrexate and pemetrexed.

Open Access

Green Accepted

Preprint

Link to Author Manuscript

Repository Citation

Golani, L., Islam, F., O'Connor, C., Dekhne, A., Hou, Z., Matherly, L., & Gangjee, A. (2020). Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier. Bioorganic and Medicinal Chemistry, 28 (12). https://doi.org/10.1016/j.bmc.2020.115544