Journal article
Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand
ACS medicinal chemistry letters, Vol.15(10), pp.1771-1777
10/10/2024
DOI: 10.1021/acsmedchemlett.4c00371
Abstract
While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS. These compounds displayed low nanomolar to high picomolar potency. Addition of a p-isopropyl group to the phenyl substituent and use of cyclohexyl or p-methoxybenzyl groups as the acyloxy substituent significantly increased human, but not mouse or rat, plasma stability without negatively impacting potency. Combinations of these prodrug moieties further improved stability, with the best combination achieving a half-life of over 12 h in human plasma, a marked improvement on prior compounds. In contrast, oxane analogs improved water solubility and cellular payload delivery but remained unstable in human plasma. The studies suggest that certain ester-based phosphonate prodrugs quickly deliver active payloads inside cells and show substantial stability in human plasma.
Details
- Title: Subtitle
- Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand
- Creators
- Umed Singh - University of IowaGirija Pawge - University of ConnecticutSarita Rani - University of ConnecticutChia-Hung Christine Hsiao - University of ConnecticutDavid F. Wiemer - University of IowaAndrew J. Wiemer - University of Connecticut
- Resource Type
- Journal article
- Publication Details
- ACS medicinal chemistry letters, Vol.15(10), pp.1771-1777
- DOI
- 10.1021/acsmedchemlett.4c00371
- ISSN
- 1948-5875
- eISSN
- 1948-5875
- Publisher
- AMER CHEMICAL SOC
- Grant note
- National Institutes of Health: CA186935, AI150869
We appreciate the assistance of Dr. Jeremy Balsbaugh, Dr. Jen Liddle, and Dr. Sonam Tamrakar at the University of Connecticut Proteomics & Metabolomics Facility with the LCMS analysis. Financial support was received from the National Institutes of Health (CA186935 and AI150869). The Q-Exactive mass spectrometer used in this research was acquired through the National Science Foundation Major Research Instrumentation and the Chemical Instrumentation Programs (CHE-1919422).
- Language
- English
- Electronic publication date
- 09/25/2024
- Date published
- 10/10/2024
- Academic Unit
- Chemistry
- Record Identifier
- 9984721247902771
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