Efficiency of bis-amidate phosphonate prodrugs.
Butyrophilin
Isoprenoid
Ligand
Phosphoantigen
Phosphonamidate prodrug
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 06 2022
15 06 2022
Historique:
received:
03
03
2022
revised:
03
04
2022
accepted:
06
04
2022
pubmed:
12
4
2022
medline:
4
5
2022
entrez:
11
4
2022
Statut:
ppublish
Résumé
Bis-amidate derivatives have been viewed as attractive phosphonate prodrug forms because of their straightforward synthesis, lack of phosphorus stereochemistry, plasma stability and nontoxic amino acid metabolites. However, the efficiency of bis-amidate prodrug forms is unclear, as prior studies on this class of prodrugs have not evaluated their activation kinetics. Here, we synthetized a small panel of bis-amidate prodrugs of butyrophilin ligands as potential immunotherapy agents. These compounds were examined relative to other prodrug forms delivering the same payload for their stability in plasma and cell lysate, their ability to stimulate T cell proliferation in human PBMCs, and their activation kinetics in a leukemia co-culture model of T cell cytokine production. The bis-amidate prodrugs demonstrate high plasma stability and improved cellular phosphoantigen activity relative to the free phosphonic acid. However, the efficiency of bis-amidate activation is low relative to other prodrugs that contain at least one ester such as aryl-amidate, aryl-acyloxyalkyl ester, and bis-acyloxyalkyl ester forms. Therefore, bis-amidate prodrugs do not drive rapid cellular payload accumulation and they would be more useful for payloads in which slower, sustained-release kinetics are preferred.
Identifiants
pubmed: 35405283
pii: S0960-894X(22)00200-1
doi: 10.1016/j.bmcl.2022.128724
pmc: PMC10245299
mid: NIHMS1902090
pii:
doi:
Substances chimiques
Esters
0
Ligands
0
Organophosphonates
0
Prodrugs
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
128724Subventions
Organisme : NIAID NIH HHS
ID : R01 AI150869
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA186935
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
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