Synthesis and structure-activity relationships of CD39 and CD73 inhibitors
Synthesis and structure-activity relationships of CD39 and CD73 inhibitors
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DissertationPrüfungsdatum
01.07.2022Datum der Veröffentlichung
13.08.2022Erstgutachter
Müller, Christa E.Zweitgutachter
Hansen, Finn KristianMetadaten
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Inhalt
Ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1 or CD39) is a member of the membrane-bound ecto-nucleotidase family, which catalyzes the extracellular hydrolysis of pro-inflammatory ATP and pro-thrombotic ADP to yield AMP. AMP is subsequently hydrolyzed by ecto-5′-nucleotidase (CD73) producing anti-inflammatory and immunosuppressive adenosine.
This study was aimed at the design, synthesis, testing and structure-activity relationship (SAR) analysis of nucleotidic, orthosteric as well as non-nucleotidic, allosteric CD39 inhibitors.
The antithrombotic prodrug ticlopidine was previously described to directly inhibit CD39 with moderate potency. In the present study, the structure of ticlopidine was extensively modified to study SARs. Structurally related tetrahydroisoquinolines proved to be similarly or even more potent CD39 inhibitors without the possibility to be metabolized to antithrombotic thiols.
In a further subproject, the 1-, 2-, 6-, 7- and 8-positions of adenosine 5′-monophosphate (AMP) were individually or jointly modified. The synthesis of the so far most potent competitive CD39 antagonist, 8-butylthio-AMP, was upscaled to allow its comprehensive pharmacological and pharmacokinetic evaluation in addition to structural studies. It was characterized as a metabolically highly stable dual inhibitor of CD39 and CD73. The combination of 8-BuS-AMP (Ki = 0.847 μM) and N6-(4-phenylbutyl)-AMP (Ki = 7.08 μM) yielded the CD39 inhibitor 8‑(butylthio)-N6-(4-phenylbutyl)-AMP (48b, Ki = 0.444 μM) showing increased potency. A further combination yielding 8-(1-naphthylthio)-N6-(4-phenylbutyl)-AMP (48e, Ki = 0.329 μM) resulted in the most potent competitive CD39 inhibitor of the present series.
A series of pyrazolopyrimidine ribonucleotides, modified in the 7-position, was synthesized and evaluated as novel, potent CD73 inhibitors with Ki values in the low nanomolar range.
Finally, potent dual CD39/CD73 inhibitors were identified in several series of nucleotide analogs. These inhibitors may act synergistically since they block the conversion of ATP all the way to adenosine, leading to an accumulation of ATP and a depletion of adenosine. Dual CD39/CD73 inhibitors are predicted to be superior to compounds inhibiting only a single target, CD39 or CD73, for the immunotherapy of cancer and infections.
This study was aimed at the design, synthesis, testing and structure-activity relationship (SAR) analysis of nucleotidic, orthosteric as well as non-nucleotidic, allosteric CD39 inhibitors.
The antithrombotic prodrug ticlopidine was previously described to directly inhibit CD39 with moderate potency. In the present study, the structure of ticlopidine was extensively modified to study SARs. Structurally related tetrahydroisoquinolines proved to be similarly or even more potent CD39 inhibitors without the possibility to be metabolized to antithrombotic thiols.
In a further subproject, the 1-, 2-, 6-, 7- and 8-positions of adenosine 5′-monophosphate (AMP) were individually or jointly modified. The synthesis of the so far most potent competitive CD39 antagonist, 8-butylthio-AMP, was upscaled to allow its comprehensive pharmacological and pharmacokinetic evaluation in addition to structural studies. It was characterized as a metabolically highly stable dual inhibitor of CD39 and CD73. The combination of 8-BuS-AMP (Ki = 0.847 μM) and N6-(4-phenylbutyl)-AMP (Ki = 7.08 μM) yielded the CD39 inhibitor 8‑(butylthio)-N6-(4-phenylbutyl)-AMP (48b, Ki = 0.444 μM) showing increased potency. A further combination yielding 8-(1-naphthylthio)-N6-(4-phenylbutyl)-AMP (48e, Ki = 0.329 μM) resulted in the most potent competitive CD39 inhibitor of the present series.
A series of pyrazolopyrimidine ribonucleotides, modified in the 7-position, was synthesized and evaluated as novel, potent CD73 inhibitors with Ki values in the low nanomolar range.
Finally, potent dual CD39/CD73 inhibitors were identified in several series of nucleotide analogs. These inhibitors may act synergistically since they block the conversion of ATP all the way to adenosine, leading to an accumulation of ATP and a depletion of adenosine. Dual CD39/CD73 inhibitors are predicted to be superior to compounds inhibiting only a single target, CD39 or CD73, for the immunotherapy of cancer and infections.
Schlagwörter
synthesis, CD39, CD73, inhibitors, ticlopidine, nucleotides, 8-BuS-AMP, 7-deaza-AMP, AMPCP, pyrazolopyrimidine nucleotides, ectonucleotidases, immunotherapy
Klassifikation (DDC)
500 Naturwissenschaften 540 Chemie 610 Medizin, GesundheitBi, Chunyang: Synthesis and structure-activity relationships of CD39 and CD73 inhibitors. - Bonn, 2022. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-67548
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-67548
@phdthesis{handle:20.500.11811/10167,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-67548,
author = {{Chunyang Bi}},
title = {Synthesis and structure-activity relationships of CD39 and CD73 inhibitors},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = aug,
note = {Ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1 or CD39) is a member of the membrane-bound ecto-nucleotidase family, which catalyzes the extracellular hydrolysis of pro-inflammatory ATP and pro-thrombotic ADP to yield AMP. AMP is subsequently hydrolyzed by ecto-5′-nucleotidase (CD73) producing anti-inflammatory and immunosuppressive adenosine.
This study was aimed at the design, synthesis, testing and structure-activity relationship (SAR) analysis of nucleotidic, orthosteric as well as non-nucleotidic, allosteric CD39 inhibitors.
The antithrombotic prodrug ticlopidine was previously described to directly inhibit CD39 with moderate potency. In the present study, the structure of ticlopidine was extensively modified to study SARs. Structurally related tetrahydroisoquinolines proved to be similarly or even more potent CD39 inhibitors without the possibility to be metabolized to antithrombotic thiols.
In a further subproject, the 1-, 2-, 6-, 7- and 8-positions of adenosine 5′-monophosphate (AMP) were individually or jointly modified. The synthesis of the so far most potent competitive CD39 antagonist, 8-butylthio-AMP, was upscaled to allow its comprehensive pharmacological and pharmacokinetic evaluation in addition to structural studies. It was characterized as a metabolically highly stable dual inhibitor of CD39 and CD73. The combination of 8-BuS-AMP (Ki = 0.847 μM) and N6-(4-phenylbutyl)-AMP (Ki = 7.08 μM) yielded the CD39 inhibitor 8‑(butylthio)-N6-(4-phenylbutyl)-AMP (48b, Ki = 0.444 μM) showing increased potency. A further combination yielding 8-(1-naphthylthio)-N6-(4-phenylbutyl)-AMP (48e, Ki = 0.329 μM) resulted in the most potent competitive CD39 inhibitor of the present series.
A series of pyrazolopyrimidine ribonucleotides, modified in the 7-position, was synthesized and evaluated as novel, potent CD73 inhibitors with Ki values in the low nanomolar range.
Finally, potent dual CD39/CD73 inhibitors were identified in several series of nucleotide analogs. These inhibitors may act synergistically since they block the conversion of ATP all the way to adenosine, leading to an accumulation of ATP and a depletion of adenosine. Dual CD39/CD73 inhibitors are predicted to be superior to compounds inhibiting only a single target, CD39 or CD73, for the immunotherapy of cancer and infections.},
url = {https://hdl.handle.net/20.500.11811/10167}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-67548,
author = {{Chunyang Bi}},
title = {Synthesis and structure-activity relationships of CD39 and CD73 inhibitors},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2022,
month = aug,
note = {Ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1 or CD39) is a member of the membrane-bound ecto-nucleotidase family, which catalyzes the extracellular hydrolysis of pro-inflammatory ATP and pro-thrombotic ADP to yield AMP. AMP is subsequently hydrolyzed by ecto-5′-nucleotidase (CD73) producing anti-inflammatory and immunosuppressive adenosine.
This study was aimed at the design, synthesis, testing and structure-activity relationship (SAR) analysis of nucleotidic, orthosteric as well as non-nucleotidic, allosteric CD39 inhibitors.
The antithrombotic prodrug ticlopidine was previously described to directly inhibit CD39 with moderate potency. In the present study, the structure of ticlopidine was extensively modified to study SARs. Structurally related tetrahydroisoquinolines proved to be similarly or even more potent CD39 inhibitors without the possibility to be metabolized to antithrombotic thiols.
In a further subproject, the 1-, 2-, 6-, 7- and 8-positions of adenosine 5′-monophosphate (AMP) were individually or jointly modified. The synthesis of the so far most potent competitive CD39 antagonist, 8-butylthio-AMP, was upscaled to allow its comprehensive pharmacological and pharmacokinetic evaluation in addition to structural studies. It was characterized as a metabolically highly stable dual inhibitor of CD39 and CD73. The combination of 8-BuS-AMP (Ki = 0.847 μM) and N6-(4-phenylbutyl)-AMP (Ki = 7.08 μM) yielded the CD39 inhibitor 8‑(butylthio)-N6-(4-phenylbutyl)-AMP (48b, Ki = 0.444 μM) showing increased potency. A further combination yielding 8-(1-naphthylthio)-N6-(4-phenylbutyl)-AMP (48e, Ki = 0.329 μM) resulted in the most potent competitive CD39 inhibitor of the present series.
A series of pyrazolopyrimidine ribonucleotides, modified in the 7-position, was synthesized and evaluated as novel, potent CD73 inhibitors with Ki values in the low nanomolar range.
Finally, potent dual CD39/CD73 inhibitors were identified in several series of nucleotide analogs. These inhibitors may act synergistically since they block the conversion of ATP all the way to adenosine, leading to an accumulation of ATP and a depletion of adenosine. Dual CD39/CD73 inhibitors are predicted to be superior to compounds inhibiting only a single target, CD39 or CD73, for the immunotherapy of cancer and infections.},
url = {https://hdl.handle.net/20.500.11811/10167}
}
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