Journal article
Efficiency of bis-amidate phosphonate prodrugs
Bioorganic & medicinal chemistry letters, Vol.66, 128724
04/08/2022
DOI: 10.1016/j.bmcl.2022.128724
PMCID: PMC10245299
PMID: 35405283
Abstract
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.
Details
- Title: Subtitle
- Efficiency of bis-amidate phosphonate prodrugs
- Creators
- Nicholas A Lentini - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United StatesXueting Huang - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, United StatesMegan A Schladetsch - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, United StatesChia-Hung Christine Hsiao - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, United StatesDavid F Wiemer - University of IowaAndrew J Wiemer - University of Connecticut
- Resource Type
- Journal article
- Publication Details
- Bioorganic & medicinal chemistry letters, Vol.66, 128724
- DOI
- 10.1016/j.bmcl.2022.128724
- PMID
- 35405283
- PMCID
- PMC10245299
- NLM abbreviation
- Bioorg Med Chem Lett
- eISSN
- 1464-3405
- Language
- English
- Date published
- 04/08/2022
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9984241029802771
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