Development of a p-hydroxybenzyl-alcohol-linked glutamate prodrug for activation by pseudomonas carboxypeptidase G2 Journal Article
| Authors: | Lee, J. P.; Corless, B. C.; Gardner, T. J.; Scheinberg, D. A.; Tan, D. S. |
| Article Title: | Development of a p-hydroxybenzyl-alcohol-linked glutamate prodrug for activation by pseudomonas carboxypeptidase G2 |
| Abstract: | Directed enzyme-prodrug therapies used for targeted drug delivery require prodrugs that are chemically stable and processed efficiently by the activating enzyme. We recently reported the development of AMS-6-Glu (2), a glutamate-masked version of the cytotoxic natural product 5′-O-sulfamoyladenosine (AMS, 1) that can be activated by Pseudomonas carboxypeptidase G2 (CPG2). Herein, we report the development of a second-generation prodrug, AMS-5′-PHOBA-Glu (5), that undergoes cleavage by CPG2 with >160-fold higher efficiency. Use of a p-hydroxybenzyl alcohol (PHOBA) self-immolative linker overcame unexpected chemical instability observed with a conventional p-aminobenzyl alchohol (PABA) linker. © 2023 American Chemical Society. All rights reserved. |
| Keywords: | antineoplastic agents; antineoplastic agent; drug delivery systems; glutamic acid; drug delivery system; prodrug; prodrugs; gamma-glutamyl hydrolase; gamma glutamyl hydrolase |
| Journal Title: | Organic Letters |
| Volume: | 25 |
| Issue: | 34 |
| ISSN: | 1523-7060 |
| Publisher: | American Chemical Society |
| Date Published: | 2023-09-01 |
| Start Page: | 6295 |
| End Page: | 6299 |
| Language: | English |
| DOI: | 10.1021/acs.orglett.3c02130 |
| PUBMED: | 37602700 |
| PROVIDER: | scopus |
| PMCID: | PMC10543097 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Derek Tan -- Source: Scopus |
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