Third‐Generation CD73 Inhibitors Based on a 4,6‐Disubstituted‐2‐Thiopyridine Scaffold

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein. Using a functional assay on immune cells, few compounds belonging to series 4 were shown to be able to antagonize the inhibition of the T-cell proliferation at both 100 μM and 10 μM (completely for 4 ab and partially for 4 ai), that is as potent as AOPCP which entirely reversed the inhibitory impact of exogenous ATP on T cell proliferation until 62.5 μM. In addition, we have shown that both compounds (4 ab and 4 ai) were also capable of moderately inhibiting the hA<sub>2A</sub> receptor with Ki in the μmolar range in HEK-293 cells. Thus, with the aim to reduce the molecular size and the lipophilicity of our initial scaffold, we finally observed by serendipity a modification of the potential target of our compounds.

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Journal
ChemMedChem
Published
2024-12-13
DOI
https://doi.org/10.1002/cmdc.202400662
Citations
1
Primary Topic
Adenosine and Purinergic Signaling
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article
Field-Weighted Citation Impact
0.40

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article

Third‐Generation CD73 Inhibitors Based on a 4,6‐Disubstituted‐2‐Thiopyridine Scaffold

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article

Third‐Generation CD73 Inhibitors Based on a 4,6‐Disubstituted‐2‐Thiopyridine Scaffold

Aurélien Lebrun, Jean‐Pierre Uttaro, Félix Grosjean, Christine Ménétrier‐Caux, Laurent Chaloin, Suzanne Peyrottes, Lars Petter Jordheim, Rayane Ghoteimi, Christophe Mathé, Emeline Cros‐Perrial, Kenneth A. Jacobson, Céline Rodriguez, Zhan-Guo Gao, Maria Shaldaeva
article en
1 citations

Abstract

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein. Using a functional assay on immune cells, few compounds belonging to series 4 were shown to be able to antagonize the inhibition of the T-cell proliferation at both 100 μM and 10 μM (completely for 4 ab and partially for 4 ai), that is as potent as AOPCP which entirely reversed the inhibitory impact of exogenous ATP on T cell proliferation until 62.5 μM. In addition, we have shown that both compounds (4 ab and 4 ai) were also capable of moderately inhibiting the hA<sub>2A</sub> receptor with Ki in the μmolar range in HEK-293 cells. Thus, with the aim to reduce the molecular size and the lipophilicity of our initial scaffold, we finally observed by serendipity a modification of the potential target of our compounds.

ChemMedChemVol. 20(6)
Université Claude Bernard Lyon 1 (FR), École Nationale Supérieure de Chimie de Montpellier (FR), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Inserm (FR), Université de Montpellier (FR), Centre Léon Bérard (FR), Centre de Recherche en Cancérologie de Lyon (FR), Délégation Languedoc Roussillon (FR), Institut de Recherche en Infectiologie de Montpellier (FR), Institut des Biomolécules Max Mousseron (FR)
Institut National Du Cancer, Université de Montpellier, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 33%
Adenosine and Purinergic Signaling
0.40
DOIOpen Access PDFOpenAlex
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