Synthesis and Metabolism of BTN3A1 Ligands: Studies on Modifications of the Allylic Alcohol.

Autor:	Lentini NA; Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States., Schroeder CM; Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States., Harmon NM; Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States., Huang X; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United States., Schladetsch MA; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United States., Foust BJ; Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States., Poe MM; Department of Chemistry, Western Michigan University, Kalamazoo, Michigan 49008-5413, United States., Hsiao CC; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United States., Wiemer AJ; Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United States.; Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut 06269-3092, United States., Wiemer DF; Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States.; Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242-1109, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Dec 04; Vol. 12 (1), pp. 136-142. Date of Electronic Publication: 2020 Dec 04 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.0c00586
Abstrakt:	( E )-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) and its phosphonate analogs are potent phosphoantigens. HMBPP contains an ( E )-allylic alcohol which interacts with the molecular target BTN3A1 giving an antigenic signal to activate Vγ9Vδ2 T cells. As probes of BTN3A1 function, we prepared prodrug derivatives of the HMBPP analog C-HMBP that lack the ( E )-allylic alcohol or have modified it to an aldehyde or aldoxime and evaluated their biological activity. Removal of the alcohol completely abrogates phosphoantigenicity in these compounds while the aldoxime modification decreases potency relative to the ( E )-allylic alcohol form. However, homoprenyl derivatives oxidized to an aldehyde stimulate Vγ9Vδ2 T cells at nanomolar concentrations. Selection of phosphonate protecting groups (i.e., prodrug forms) impacts the potency of phosphoantigen aldehydes, with mixed aryl acyloxyalkyl forms exhibiting superior activity relative to aryl amidate forms. The activity correlates with the cellular reduction of the aldehyde to the alcohol form. Thus, the functionality on this ligand framework can be altered concurrently with phosphonate protection to promote cellular transformation to highly potent phosphoantigens. Competing Interests: The authors declare the following competing financial interest(s): A.J.W. and D.F.W. own shares in Terpenoid Therapeutics, Inc. The current work did not involve the company. The other authors have no financial conflicts of interest. (© 2020 American Chemical Society.)
Databáze:	MEDLINE
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