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Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the A3 and the P2Y2 Purinergic Receptors

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Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the A3 and the P2Y2 Purinergic Receptors Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the A3 and the P2Y2 Purinergic Receptors Apr. Liesbet Cosyn Thesis submitted to the Faculty of Pharmaceutical Sciences to obtain the degree of Doctor in Pharmaceutical Sciences Promoter Prof. dr. apr. Serge Van Calenbergh Academic year 2007-2008 TABLE OF CONTENTS 1 INTRODUCTION ................................................................................................. 3 1.1 Purinergic Receptors ................................................................................. 3 1.2 Adenosine Analogues and the Adenosine A3 Receptor ......................... 4 1.2.1 Adenosine................................................................................................. 4 1.2.2 The Adenosine Receptors: G-protein-Coupled Receptors........................ 7 1.2.3 Adenosine Receptor Subtypes and Their Signalling............................... 10 1.2.4 The Adenosine A3 Receptor ................................................................... 12 1.2.4.1 Adenosine A3 Receptor Agonists ................................................. 12 1.2.4.2 Adenosine A3 Receptor Antagonists ............................................ 16 1.2.4.3 Allosteric Modulation.................................................................... 21 1.2.4.4 Molecular Modeling of the Adenosine A3 Receptor...................... 22 1.2.4.5 The Neoceptor concept................................................................ 23 1.2.4.6 Therapeutic Potential of A3AR Agonists....................................... 25 1.2.4.7 Therapeutic Potential of A3AR Antagonists.................................. 27 1.3 Pyrimidine Nucleotides And The P2Y2 Receptor................................... 29 1.3.1 Uracil And Adenine Nucleotides ............................................................. 29 1.3.2 The P2Y Receptors................................................................................. 30 1.3.2.1 The P2 Receptor Family .............................................................. 30 1.3.2.2 The P2Y Receptor Subtypes and their Signalling ........................ 31 1.3.3 The P2Y2 Receptor................................................................................. 33 1.3.3.1 P2Y2 Receptor Agonists............................................................... 33 1.3.3.2 P2Y2 receptor Antagonists ........................................................... 38 1.3.3.3 Molecular Modeling of the P2Y2 Receptor.................................... 41 1.3.3.4 Therapeutic Potential of P2Y2 Receptor Agonists........................ 43 1.3.3.5 Therapeutic Potential of P2Y2 Receptor Antagonists................... 46 1.4 Objectives and Structure of this Thesis................................................. 47 1.5 Note on the Nucleoside Nomenclature Used in this Work.................... 49 2 HYPERMODIFIED ADENOSINE ANALOGUES............................................... 53 2.1 Introduction .............................................................................................. 53 2.2 Chemistry.................................................................................................. 54 2.2.1 Synthesis of 5’-N-Methyluronamide 2-Phenylacetylene Adenosine Derivatives 2.7, 2.9 and 2.20............................................................................. 54 2.2.2 Synthesis of 2-Alkynylated 3’-Amino-adenosines 2.3-2.5 ....................... 58 2.2.3 Synthesis of Other 2-Substituted Adenosine Derivatives........................ 59 2.2.4 Mechanism of the Vorbrüggen Coupling Reaction.................................. 60 2.3 Biological Evaluation ............................................................................... 61 2.4 Conclusions.............................................................................................. 63 3 2-TRIAZOLE-SUBSTITUTED ADENOSINE ANALOGUES ............................. 69 3.1 Introduction .............................................................................................. 69 3.2 Chemistry.................................................................................................. 71 3.2.1 Synthesis of 2-[(1,2,3)-Triazol-1-yl]adenosine Derivatives 3.1-3.11........ 71 3.2.2 Synthesis of 2-[(1,2,3)-Triazol-4-yl]adenosine Derivatives 3.12-3.14...... 73 i 3.2.3 Synthesis of 5’-Uronamide-2-[(1,2,3)-triazol-1-yl]adenosine Analogues 3.15a,b-3.19a,b ................................................................................................. 74 3.2.4 Synthesis of Compound 3.20.................................................................. 76 3.2.5 Mechanism of the Cu(I) Catalyzed [3+2]Cycloaddition of Azides and Alkynes.............................................................................................................. 77 3.3 Biological Evaluation ............................................................................... 79 3.4 Molecular Modeling.................................................................................. 85 3.5 Conclusions.............................................................................................. 88 4 PYRIMIDINE NUCLEOTIDE ANALOGUES ..................................................... 93 4.1 Synthesis And Evaluation of 2-Thio UTP Derivatives 4.1-4.5............... 93 4.1.1 Introduction............................................................................................. 93 4.1.2 Chemistry................................................................................................ 94 4.1.2.1 Synthesis of 2-Thiouridine 4.12.................................................... 94 4.1.2.2 Synthesis of 2’-Amino-2’-deoxy 2-thiouridine 4.33 ....................... 97 4.1.2.3 Attempts to Synthesize Other 2’-Substituted 2-Thiouridine Derivatives………………................................................................................ 99 4.1.2.4 5’-Phosphorylation of 2-Thio Uridine Derivatives 4.1-4.4 ........... 103 4.1.2.5 Synthesis of 2,4-Dithiouridine and Phosphorylation Attempt: Synthesis of 4-Methylthio Analogue 4.5....................................................... 104 4.1.3 Biological Evaluation............................................................................. 105 4.1.4 Molecular Modeling............................................................................... 107 4.1.5 Conclusions .......................................................................................... 110 4.2 Synthesis and Evaluation of Uridine 5’-Phosphonodiphosphates 4.6 and 4.7................................................................................................................ 111 4.2.1 Introduction........................................................................................... 111 4.2.2 Synthesis .............................................................................................. 112 4.2.2.1 Synthesis of Uridine 5’-Phosphonodiphosphates 4.6 and 4.7.... 112 4.2.2.2 Attempts to Synthesize 2-Thiouridine 5’- Phosphonodiphosphate ............................................................................... 113 4.2.3 Biological Evaluation............................................................................. 117 4.2.4 Conclusions .......................................................................................... 119 5 EXPERIMENTAL SECTION ........................................................................... 125 5.1 Synthesis ................................................................................................ 125 5.1.1 General................................................................................................. 125 5.1.2 Hypermodified Adenosine Analogues................................................... 126 5.1.3 2-Triazol-Substituted Adenosine Analogues......................................... 145 5.1.4 Pyrimidine Nucleotide Analogues ......................................................... 171 5.2 Binding Studies...................................................................................... 200 5.2.1 Binding studies at the A3AR.................................................................. 200 5.2.1.1 Cell Culture and Membrane Preparation.................................... 200 5.2.1.2 Radioligand Binding Studies ...................................................... 200 5.2.1.3 Cyclic AMP Accumulation Assay ............................................... 201 35 5.2.1.4 [ S]GTPγS binding assay.......................................................... 202 5.2.2 Binding Studies at the P2Y2 Receptor .................................................. 203 5.2.2.1 Assay of PLC Activity Stimulated by P2Y2, P2Y4, and P2Y6 Receptors……….......................................................................................... 203 ii 5.3 Molecular modeling and docking.......................................................... 204 5.3.1 Docking Studies of Compound 3.10 ..................................................... 204 5.3.2 Molecular Modeling of the P2Y2 Receptor ............................................ 206 5.3.2.1 Molecular Modeling.................................................................... 206 5.3.2.2 Molecular Dynamics Simulation of the P2Y2 Receptor............... 207 5.3.2.3 Manual Molecular Docking......................................................... 207 5.3.2.4 Conformational Analysis of UTP, ATP and Their Derivatives..... 208 6 REFERENCES................................................................................................ 209 iii iv Dankwoord
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