Potent double prodrug forms of synthetic phosphoantigens

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

doi:10.1016/j.bmc.2020.115666

Cited by 6 publications

(7 citation statements)

References 38 publications

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“…Additionally, the protection of the allylic alcohol in aryloxy diester phosphonamidate prodrugs with a biocleavable protecting group such as the acetate ester (compound 65 ) increased their potency compared to their free alcohol counterparts and to HMBPP [ 117 ].…”

Section: Mep Pathway As Immunostimulant Sourcementioning

confidence: 99%

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

et al. 2023

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Isoprenoids, a diverse class of natural products, are present in all living organisms. Their two universal building blocks are synthesized via two independent pathways: the mevalonate pathway and the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. The presence of the latter in pathogenic bacteria and its absence in humans make all its enzymes suitable targets for the development of novel antibacterial drugs. (E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), the last intermediate of this pathway, is a natural ligand for the human Vγ9Vδ2 T cells and the most potent natural phosphoantigen known to date. Moreover, 5-hydroxypentane-2,3-dione, a metabolite produced by Escherichia coli 1-deoxy-d-xylulose 5-phosphate synthase (DXS), the first enzyme of the MEP pathway, structurally resembles (S)-4,5-dihydroxy-2,3-pentanedione, a signal molecule implied in bacterial cell communication. In this review, we shed light on the diversity of potential uses of the MEP pathway in antibacterial therapies, starting with an overview of the antibacterials developed for each of its enzymes. Then, we provide insight into HMBPP, its synthetic analogs, and their prodrugs. Finally, we discuss the potential contribution of the MEP pathway to quorum sensing mechanisms. The MEP pathway, providing simultaneously antibacterial drug targets and potent immunostimulants, coupled with its potential role in bacterial cell–cell communication, opens new therapeutic perspectives.

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Section: Mep Pathway As Immunostimulant Sourcementioning

confidence: 99%

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

et al. 2023

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“…Among them, some drug molecules containing P(O)–N bond are extraordinary frameworks and attract great interest because of their extensive physiological and pharmacological activities in medicinal chemistry . For example, remdesivir ( I ) is a famous anti-COVID-19 drug (Figure ), compound ( II ) can be employed as an anticancer agent by stimulating γδ T cell proliferation, compound ( III ) exhibits potential antibacterial and antifungal activities, and fosaprepitant ( IV ) is an antiemetic drug. , …”

Section: Introductionmentioning

confidence: 99%

Copper-Catalyzed Phosphorylation of N,N-Disubstituted Hydrazines: Synthesis of Multisubstituted Phosphorylhydrazides as Potential Anticancer Agents

et al. 2022

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An efficient copper-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction for the synthesis of multisubstituted phosphorylhydrazides from N,N-disubstituted hydrazines and hydrogen phosphoryl compounds is accomplished. The reaction proceeds under mild conditions without the addition of any external oxidants and bases. This work reported here represents a direct P(O)–N–N bond formation with the advantages of being operationally simple, good functional group tolerance, and high atom and step economy. Furthermore, the selected compounds exhibit potential inhibitory activity against tumor cells, which can be used in the field of screening of anticancer agents as new chemical entities.

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“…25 Taken together, three novel diene prodrugs (8, 9, and 24) have pAg activity at mid-nanomolar concentrations. Whereas this is less potent than the picomolar activity of the best prodrugs, 20,26,31 these dienes still have significant activity.…”

mentioning

confidence: 96%

“…We next sought to synthesize a novel diene containing an allylic alcohol as a free phosphonic acid along with a corresponding prodrug. For this prodrug, we chose to simplify the synthesis through use of acetate protection at the allylic alcohol, a group that we have shown is biologically labile . Alcohol 10 first was converted to the corresponding aldehyde 11 (Scheme ).…”

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confidence: 99%

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Synthesis and Metabolism of BTN3A1 Ligands: Studies on Diene Modifications to the Phosphoantigen Scaffold

Harmon

Huang

Singh

et al. 2022

ACS Med. Chem. Lett.

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Phosphoantigens (pAgs) are small organophosphorus compounds such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) that trigger an immune response. These molecules bind to butyrophilin 3A1 (part of the HMBPP receptor) and activate Vγ9Vδ2 T cells. To explore the structure–activity relationships underlying this process, we evaluated a series of novel diene analogs of HMBPP. Here we report that prodrug forms of [(1E)-4-methylpenta-1,3-dien-1-yl] phosphonic acid that lack the allylic alcohol of HMBPP but instead contained a diene scaffold exhibit mid-nanomolar potency for the activation of Vγ9Vδ2 T cells. The compounds also trigger the production of T-cell interferon γ upon exposure to loaded K562 cells. Although both the allylic alcohol and the diene scaffold boost pAg activity, the combination of the two decreases the activity and results in glutathione conjugation. Together, these data show that the diene scaffold results in intermediate pAgs that may have implications for the mechanisms regulating the HMBPP receptor.

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Potent double prodrug forms of synthetic phosphoantigens

Cited by 6 publications

References 38 publications

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

The Multifaceted MEP Pathway: Towards New Therapeutic Perspectives

Copper-Catalyzed Phosphorylation of N,N-Disubstituted Hydrazines: Synthesis of Multisubstituted Phosphorylhydrazides as Potential Anticancer Agents

Synthesis and Metabolism of BTN3A1 Ligands: Studies on Diene Modifications to the Phosphoantigen Scaffold

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