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Design and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists

dc.contributor.advisorMüller, Christa E.
dc.contributor.authorTemirak, Ahmed Mohamed Abbas
dc.date.accessioned2020-10-27T13:51:20Z
dc.date.available2023-11-01T23:00:18Z
dc.date.issued27.10.2020
dc.identifier.urihttps://hdl.handle.net/20.500.11811/8736
dc.description.abstractA2A 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.
en
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subject.ddc500 Naturwissenschaften
dc.subject.ddc615 Pharmakologie, Therapeutik
dc.titleDesign and Synthesis of A2B- and Dual-Acting A2A/A2B Adenosine Receptor Antagonists
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsopenAccess
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-60115
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID6011
ulbbnediss.date.accepted13.10.2020
ulbbnediss.instituteMathematisch-Naturwissenschaftliche Fakultät : Fachgruppe Pharmazie / Pharmazeutisches Institut
ulbbnediss.fakultaetMathematisch-Naturwissenschaftliche Fakultät
dc.contributor.coRefereeHansen, Finn
ulbbnediss.contributor.orcidhttps://orcid.org/0000-0003-3862-5359
ulbbnediss.date.embargoEndDate01.11.2023
ulbbnediss.date.embargoEndDate01.11.2023


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