Incorporation of a FRET pair within a phosphonate diester

Harmon, Nyema M.; Huang, Xueting; Hsiao, Chia‐Hung Christine; Wiemer, Andrew J.; Wiemer, David F.

doi:10.1016/j.bioorg.2021.105048

Cited by 4 publications

(5 citation statements)

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“…One key study reported a 40-fold variation in the rate of hydrolysis as a function of the acyl group incorporated in the acyloxymethyl ester . To initiate investigation of this factor, we selected acyl groups at the extremes of stability and lability from the work of Dickson et al Thus, benzoic acid (R x ), isobutyric acid (R y ), and cyclohexylacetic acid (R z ) were converted to their respective chloromethyl esters through reaction with chloromethyl chlorosulfate, , and the resulting reagents were used to prepare the respective acyloxymethyl esters 10x – z of phosphonate 6a (Scheme ). After installation of the acyloxymethyl group, oxidation with selenium dioxide was used to introduce the allylic alcohols (i.e., 11x – z ), and a final reaction with acetic anhydride gave the double prodrugs 12x – z .…”

Section: Resultsmentioning

confidence: 99%

Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

Singh,

Pawge,

Rani

et al. 2023

J. Med. Chem.

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Activation of Vγ9Vδ2 T cells with butyrophilin 3A1 (BTN3A1) agonists such as ( E )-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) has the potential to boost the immune response. Because HMBPP is highly charged and metabolically unstable, prodrugs may be needed to overcome these liabilities, but the prodrugs themselves may be limited by slow payload release or low plasma stability. To identify effective prodrug forms of a phosphonate agonist of BTN3A1, we have prepared a set of diesters bearing one aryl and one acyloxymethyl group. The compounds were evaluated for their ability to stimulate Vγ9Vδ2 T cell proliferation, increase production of interferon γ, resist plasma metabolism, and internalize into leukemia cells. These bioassays have revealed that varied aryl and acyloxymethyl groups can decouple plasma and cellular metabolism and have a significant impact on bioactivity (>200-fold range) and stability (>10 fold range), including some with subnanomolar potency. Our findings increase the understanding of the structure–activity relationships of mixed aryl/acyloxymethyl phosphonate prodrugs.

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Section: Resultsmentioning

confidence: 99%

Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

Singh,

Pawge,

Rani

et al. 2023

J. Med. Chem.

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“…In another example of phosphonate-mediated cleavage, Wiemer et al reported a similar coumarin diphosphate analogue to release a prodrug upon internalization to stimulate the immune response of human Vg9Vd2 T cells. 34 Again, K562 cells pre-loaded with the probe were able to trigger Vg9Vd2 T cell-mediated killing (EC 50 : 180 nM).…”

Section: T Cell Migration Tracers and Probes Targeting T Cell Metabolismmentioning

confidence: 96%

Section: Fluorescent Probes For Live-cell Imaging Of Gpcrsmentioning

confidence: 99%

“…3c ). 34 Notably, when the probe was added to K562 leukaemia cells and subsequently cultured with γδ T cells, the cleavage of the ligand cargo promoted cytokine production by γδ T cells (EC 50 : 0.69 nM). In another example of phosphonate-mediated cleavage, Wiemer et al reported a similar coumarin diphosphate analogue to release a prodrug upon internalization to stimulate the immune response of human Vg9Vd2 T cells.…”

Section: T Cell Migration Tracers and Probes Targeting T Cell Metabolismmentioning

confidence: 99%

“…Enzymatic cleavage of the phosphonate bond triggers the release of the quencher and the BTN3A-1 agonist, resulting in a dose dependent increase in fluorescence intensity and cell activation. Reproduced from ref 34. with permission from Elsevier, copyright 2021.…”

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confidence: 99%

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Smart probes for optical imaging of T cells and screening of anti-cancer immunotherapies

et al. 2023

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Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand

Singh,

Pawge,

Rani

et al. 2024

ACS Med. Chem. Lett.

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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.

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Incorporation of a FRET pair within a phosphonate diester

Cited by 4 publications

References 40 publications

Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

Smart probes for optical imaging of T cells and screening of anti-cancer immunotherapies

Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand

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