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Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the a 3 and the P2Y 2 Purinergic Receptors

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Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the a 3 and the P2Y 2 Purinergic Receptors Synthesis and Biological Evaluation of Purine and Pyrimidine Based Ligands for the A 3 and the P2Y 2 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 A 3 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 A 3 Receptor ................................................................... 12 1.2.4.1 Adenosine A 3 Receptor Agonists ................................................. 12 1.2.4.2 Adenosine A 3 Receptor Antagonists ............................................ 16 1.2.4.3 Allosteric Modulation.................................................................... 21 1.2.4.4 Molecular Modeling of the Adenosine A 3 Receptor...................... 22 1.2.4.5 The Neoceptor concept................................................................ 23 1.2.4.6 Therapeutic Potential of A 3AR Agonists....................................... 25 1.2.4.7 Therapeutic Potential of A 3AR Antagonists.................................. 27 1.3 Pyrimidine Nucleotides And The P2Y 2 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 P2Y 2 Receptor................................................................................. 33 1.3.3.1 P2Y 2 Receptor Agonists............................................................... 33 1.3.3.2 P2Y 2 receptor Antagonists ........................................................... 38 1.3.3.3 Molecular Modeling of the P2Y 2 Receptor.................................... 41 1.3.3.4 Therapeutic Potential of P2Y 2 Receptor Agonists........................ 43 1.3.3.5 Therapeutic Potential of P2Y 2 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 A 3AR.................................................................. 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]GTP γS binding assay.......................................................... 202 5.2.2 Binding Studies at the P2Y 2 Receptor .................................................. 203 5.2.2.1 Assay of PLC Activity Stimulated by P2Y 2, P2Y 4, and P2Y 6 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 P2Y 2 Receptor ............................................ 206 5.3.2.1 Molecular Modeling.................................................................... 206 5.3.2.2 Molecular Dynamics Simulation of the P2Y 2 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...............................................................................................
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