Design and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists
Design and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists
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DissertationDate of Exam
13.10.2020Date of Publication
27.10.2020Advisor
Müller, Christa E.Co-Referee
Hansen, FinnMetadata
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Abstract
A2A and A2B adenosine receptors (ARs) are novel drug targets in cancer (immuno)therapy. Activation of A2AARs expressed on the surface of many immune cells such as T-lymphocytes and natural killer (NK) cells decreases cytokine production causing immunosuppression. A2BARs promote tumor proliferation, angiogenesis, metastasis, and also mediate immunosuppression by acting on myeloid cells. Therefore, targeting of both AR subtypes, A2A and A2B, is highly promising for cancer (immuno)therapy.
In the first subproject, we tackled the challenge of poorly water-soluble A2BAR antagonists by developing water-soluble phosphate prodrugs. We developed three series of xanthine-derived A2BAR antagonists bearing a hydroxy group attached to different positions of the scaffold. The most potent and selective A2BAR antagonists were subsequently phosphorylated to obtain the desired phosphate prodrugs, which display greatly improved water-solubility. These compounds are anticipated to become useful pharmacological tools for in vivo studies, e.g. in animal models of cancer and infections, and have potential as future drugs.
The second subproject focused on the development of potent dual-acting A2A/A2BAR antagonists. Such compounds are expected to block the immunosuppressive, pro-proliferative, angiogenic and metastasis-inducing effects of adenosine mediated through A2A- and A2BARs expressed on a broad range of immune cells as well as tumour cells. We modified the structure of the potent A2BAR antagonist PSB-1901 through various ring replacements and substitutions that were expected to increase the compounds’ potency at A2AARs without significantly reducing A2BAR affinity. The developed dual A2A/A2BAR antagonists showed high selectivity versus A1- and A3AR subtypes. Preliminary data indicated that they display physicochemical and pharmacokinetic properties suitable for therapeutic application. The new A2A/A2BAR antagonists may become drugs for cancer (immnuo)therapy and for the immunotherapy of infectious diseases.
In the first subproject, we tackled the challenge of poorly water-soluble A2BAR antagonists by developing water-soluble phosphate prodrugs. We developed three series of xanthine-derived A2BAR antagonists bearing a hydroxy group attached to different positions of the scaffold. The most potent and selective A2BAR antagonists were subsequently phosphorylated to obtain the desired phosphate prodrugs, which display greatly improved water-solubility. These compounds are anticipated to become useful pharmacological tools for in vivo studies, e.g. in animal models of cancer and infections, and have potential as future drugs.
The second subproject focused on the development of potent dual-acting A2A/A2BAR antagonists. Such compounds are expected to block the immunosuppressive, pro-proliferative, angiogenic and metastasis-inducing effects of adenosine mediated through A2A- and A2BARs expressed on a broad range of immune cells as well as tumour cells. We modified the structure of the potent A2BAR antagonist PSB-1901 through various ring replacements and substitutions that were expected to increase the compounds’ potency at A2AARs without significantly reducing A2BAR affinity. The developed dual A2A/A2BAR antagonists showed high selectivity versus A1- and A3AR subtypes. Preliminary data indicated that they display physicochemical and pharmacokinetic properties suitable for therapeutic application. The new A2A/A2BAR antagonists may become drugs for cancer (immnuo)therapy and for the immunotherapy of infectious diseases.
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500 Naturwissenschaften 615 Pharmakologie, TherapeutikTemirak, Ahmed Mohamed Abbas: Design and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists. - Bonn, 2020. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-60115
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-60115
@phdthesis{handle:20.500.11811/8736,
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-60115,
author = {{Ahmed Mohamed Abbas Temirak}},
title = {Design and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2020,
month = oct,
note = {A2A and A2B adenosine receptors (ARs) are novel drug targets in cancer (immuno)therapy. Activation of A2AARs expressed on the surface of many immune cells such as T-lymphocytes and natural killer (NK) cells decreases cytokine production causing immunosuppression. A2BARs promote tumor proliferation, angiogenesis, metastasis, and also mediate immunosuppression by acting on myeloid cells. Therefore, targeting of both AR subtypes, A2A and A2B, is highly promising for cancer (immuno)therapy.
In the first subproject, we tackled the challenge of poorly water-soluble A2BAR antagonists by developing water-soluble phosphate prodrugs. We developed three series of xanthine-derived A2BAR antagonists bearing a hydroxy group attached to different positions of the scaffold. The most potent and selective A2BAR antagonists were subsequently phosphorylated to obtain the desired phosphate prodrugs, which display greatly improved water-solubility. These compounds are anticipated to become useful pharmacological tools for in vivo studies, e.g. in animal models of cancer and infections, and have potential as future drugs.
The second subproject focused on the development of potent dual-acting A2A/A2BAR antagonists. Such compounds are expected to block the immunosuppressive, pro-proliferative, angiogenic and metastasis-inducing effects of adenosine mediated through A2A- and A2BARs expressed on a broad range of immune cells as well as tumour cells. We modified the structure of the potent A2BAR antagonist PSB-1901 through various ring replacements and substitutions that were expected to increase the compounds’ potency at A2AARs without significantly reducing A2BAR affinity. The developed dual A2A/A2BAR antagonists showed high selectivity versus A1- and A3AR subtypes. Preliminary data indicated that they display physicochemical and pharmacokinetic properties suitable for therapeutic application. The new A2A/A2BAR antagonists may become drugs for cancer (immnuo)therapy and for the immunotherapy of infectious diseases.},
url = {https://hdl.handle.net/20.500.11811/8736}
}
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-60115,
author = {{Ahmed Mohamed Abbas Temirak}},
title = {Design and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2020,
month = oct,
note = {A2A and A2B adenosine receptors (ARs) are novel drug targets in cancer (immuno)therapy. Activation of A2AARs expressed on the surface of many immune cells such as T-lymphocytes and natural killer (NK) cells decreases cytokine production causing immunosuppression. A2BARs promote tumor proliferation, angiogenesis, metastasis, and also mediate immunosuppression by acting on myeloid cells. Therefore, targeting of both AR subtypes, A2A and A2B, is highly promising for cancer (immuno)therapy.
In the first subproject, we tackled the challenge of poorly water-soluble A2BAR antagonists by developing water-soluble phosphate prodrugs. We developed three series of xanthine-derived A2BAR antagonists bearing a hydroxy group attached to different positions of the scaffold. The most potent and selective A2BAR antagonists were subsequently phosphorylated to obtain the desired phosphate prodrugs, which display greatly improved water-solubility. These compounds are anticipated to become useful pharmacological tools for in vivo studies, e.g. in animal models of cancer and infections, and have potential as future drugs.
The second subproject focused on the development of potent dual-acting A2A/A2BAR antagonists. Such compounds are expected to block the immunosuppressive, pro-proliferative, angiogenic and metastasis-inducing effects of adenosine mediated through A2A- and A2BARs expressed on a broad range of immune cells as well as tumour cells. We modified the structure of the potent A2BAR antagonist PSB-1901 through various ring replacements and substitutions that were expected to increase the compounds’ potency at A2AARs without significantly reducing A2BAR affinity. The developed dual A2A/A2BAR antagonists showed high selectivity versus A1- and A3AR subtypes. Preliminary data indicated that they display physicochemical and pharmacokinetic properties suitable for therapeutic application. The new A2A/A2BAR antagonists may become drugs for cancer (immnuo)therapy and for the immunotherapy of infectious diseases.},
url = {https://hdl.handle.net/20.500.11811/8736}
}
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