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SYNTHESIS and BIOLOGICAL Actnnry of CONFORMATIONALLY CONSTRAINED WLEOSIDES and NUCLEOTIDES

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SYNTHESIS and BIOLOGICAL Actnnry of CONFORMATIONALLY CONSTRAINED WLEOSIDES and NUCLEOTIDES SYNTHESIS AND BIOLOGICAL ACTnnrY OF CONFORMATIONALLY CONSTRAINED WLEOSIDES AND NUCLEOTIDES A thesis submitted in conformity with the requirements for the degree of Masters of Science Graduate Department of Chemistry University of Toronto National Library Bibliothèque nationaie B*m ofCanada du Canada Acquisitions and Acquisitions et Bibliographie Setvices services bibliographiques 395 Wellington Street 395. rue Wellington ûttawaON K1AW OctawaON KlAW canada canada The author has granted a non- L'auteur a accorde une licence non exclusive Licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, distn'buer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/fïlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Spthesis and Biologicai Activity of Conformationaliy Constrained NucIeosides and Nuc1eotides Degree of Master of Science, 1998 by Girolamo Tusa Graduate Department of Chemistry, University of Toronto This thesis outhes the synthesis of a variety of confonnationally constrained nucleosides and nucleotide analogues. The conformationally 'locked" analogues closely resemble specific conformers of natural nucleosides and nucieotides and were used to probe the conformationai specificity of particular physiological processes in PC 12 ce&; nucleoside transport (NT) activity and Pt-purinoceptor response. 8.2'-thioanhydroadenosine (3) and the corresponding 5'- triphosphate derivative are 'locked" in the anri-conformation about the glycosidic bond and in the S-type sugar pucker. Both characteristics are lcnown to be highly favoured conformations of adenosine and ATP in solution state. thus it is hypothesised that these endogenous compounds are recognized by NT proteins and Pz-purinoceptors in these conformations. 8,2'-thioanhydroadenosine (3) had no effect on NT activity and the triphosphate derivative did no t elicit any P2-purinoceptor responses. 2.2'-anhydrouridine (6) and the corresponding 5'- triphosphate analogue are 'locked" in the syn-conformation about the glycosidic bond and in the S-type sugar pucker. Similarly this analogue did not inhibit NT processes, although the 5'- triphosphate analogue was an agonist for the Pm-purinoceptor. 8-bromoadenosine (1) and bmercaptoadenosine (8) represent molecules with modifications on the adenioe base moiety; at concentrations of 300 pM these were found to inhibit the NT mediated uptake of [3~-adenosineby 42k2 and 58&2% of control respectively. Adenosine- 2',3'-carbonate (9) adopts a constrahed sugar pucker "intermediate" between the S and N- type sugars. This analogue was found to be a potent inhibitor of the NT process (IC5o - 10 w )* DEDICATION This thesis in dedicated to my parents who with their optimism, unrelenthg support and continuous patience have inspired me during the difEcult &es. Fist and foremost, 1 would like to acknowledge my supervisor Dr. Juta Reed. This research wouid not have ken possible without her extensive support, enthusiasm and encouragement throughout these past two years. Furthemore 1 thank her for devoting tirne to help xreen the nucleoside and nucleotide analogues and hasten the cornpietion of this work. 1 would &O like to extend my gratitude to my volunteer workers Bogdan Paun, Cathy Tusa and Mae Chimg for their diligent work in both synthesizing intermediates and screening analogues. 1 would also like to thank Dr. Sandy Raha for the selection and background research for the synthesis of 8,2'-thioanhydroadenosine (3), Dr. K. K. OgiIvie for sending the authentic sample of 8,2'-thioanhydroadenosi.ue (3). Dr. Scott Taylor for his guidance using the Varian Gemim-200 FT-NMR and Dr. Alex Young for running the FAB mass spectra of the nucleotide analogues. My thanks also go out to all the chemistry graduate students. faculty and staff, especially those at EMdak. Not only have 1 gained new fiiendships, they have ken supportive throughout my research, and wilI provide me with years of enjoyable mernories. FMy,1 wish to thank my family for their tolerance and understanding. particularIy during times of stress. TABLE OF CONTENTS ABSTRACT DEDICATION ACNOWLEGDEMENTS TABLE OF CONTENTS LIST OF TABLES LIST OF SCHEMES LIST OF FIGURES ABBREVIATIONS I. INTRODUCTION Chernical structure of nucleosides and nucleotides Metabolism of nucleosides and nucleotides 1.2.1 De novo synthesis 1.2.2 Salvage pathways 1.2.3 Catabolism Nudeoside and nucleobase transport 1.3.1 Classification of nucleuside transporter 1.3.2 Nitrobenzylthioinosine (NBn)a potent ùihibitor of equilibrative NT 1.3.3 Non-nudeoside inhibitors of equilibra rive NT 1.3.4 Rehtionships between nucleoside transport (NT) and rnetabolism 1.4 The special role of adenosine and adenine nucleotides in mammaiian ceus Il 1.4.1 Overview of PI and P~purinoceptors 12 1.5 Nucleosides as chernotherapeutic agents 1.5.1 Importance of nucleoside transport (NT) in the design and activity of nucleoside chernutherapeutics 1.6 Three-dimensional conformations of nudeosides and nucleotides 15 1.6.1 Conformations of the glycosidic bond 15 1.6.2 Confo>mations of the C(4')-C(5') exocyclic bond 18 1.6.3 Conformations of the sugar 19 1.6.4 The favoured conformation of nudeosides and nucleotides 19 1.7 The rational design of nudeoside and nucleotide inhibitors 20 1.7.1 Nucleoside seiectivities of nucleoside transport (NT) pro teins 20 1.7.2 Structure-bared synthesis of nucleoside trampon (NT) inhibiturs 22 1.7.3 Agonist specifcity of Pz-purinoceptors 24 1.7.4 Design of structure-based agonists and antagonists of Ptp~and Pm- purinoceptors 26 1.8 Physiological effects of ATP in PC12 ce& 1.9 Synthetic schemes of nucleoside and nucleotide analogs 1.9. I Syn th esis of 8.2 '-thioanhydroadenosine- 5 '-triphosphate (4) 1.9.2 Synthesis of 2.2 '-anhydrouridine-5'-triphosphate(7) 1.9.3 Synthesis of 8-mercaptoadenosine (8) 1.9.4 Synthesis of adenosine-2 :3 '-carbonate (9) II. EXPERIMENTAL PROCEDURES Materials Synthesis of nucleoside and nucleotide analogs 2.2.1 Preparation of 8.2 '-thioanhydroadenosine-5'- hiphosphate (4) 2.2.2 Preparation of 8,2 '-thioanhydroadenosine-5'- monophosphate (5) 2.2.3 Preparation of 2,2 '-anhydrouridine-5'-mphosphate (7) 2.2.4 Preparation of 8-mercaptoadenosine (8) 2.2.5 Prepararion of adenosine-2 ',3 '-carbonate (9) Ceil culture Adenosine cransport assays Determination of accumulateci adenosine and metabolities 2.7 Measurement of PC 12 ceil membrane potential with bisoxonol 2.8 Measurement of intraceilular pH in PC12 cells 2.9 Uptake of adenosine and 8,Z'-thioanhydroadenosine (3) measured by HPLC III. RESULTS AND DISCUSSION Synthetic aspects 3.1.1 Synthesis of 8.2 '-thiomrhydroademsine-5'- triphosphate (4) 3.1.2 Synthesis of 2,2 '-anhydrouridine-5'-m'phosphate (7) 3.1.3 Synrhesis of 8-mercaptuadenosine (8) 3.1 -4 Synthesis of adenosine-2 ',3 '-carbonate (9) Screening of nucleosides in PC12 ceb using the nucleoside transport assay 3.2.1 Determination of tirne course for adenosine uptake 3.2-2 Adenosine metabolism in PC12 ceils 3.2.3 Inhibition studies of NTprocesses in PC12 cells Studies on Pz-purinoceptor in PC12 ceils 3.3.1 The effects of confonnatiomlly constrathed nucieoside triphosphate malugres on P2n-purinoceptor response in PC12 cells 3.3.2 The effects of confonnationally constraUred nucleoside tnphusphate analogues on Pm-purhoceptor response in PCIZ cells 3.3.2a Meusurement of PC12 membrane potential 3.4 Future prospects and conclusions REFERENCES LIST OF TABLES 1 Classification and hinctional properties of nucleoside transporters- 7 2 Agonist "rank-order potency" proffies for some common Pz-purinoceptors 25 3 Summary of bioactivity of conformationally constmiaed nucleotide analogues 80 LIST OF SCEIl3MES 1 Synthesis of adenosine nucleotides 2 Pathways of purine nucleotide and deoxynucleotide catabolism 3 Retro-synthesis of 8,2'-thioanhydroadenosïne-5 hiphosphate (4) 4 Retro-synthesis of 2,2'-anhydroUndine-5'-uiphosphate (7) 5 Synthesis of 8,2'-thioanhydroadenosine-5 '-triphosphate (4) 6 Synthesis of 2,2'-anhydro~diae-S'-triphosphate (7) LIST OF FIGURES Chemicai structures of cornmon nucleosides Functional NT processes of mammalian ceils Structure of NBTI (nitrobenzylthioinosuie) Structures of dipyridamole @PR) and dilazep Structures of cornmon therapeutic nucleosides The syn and anri-conformation of adenosine and uridine Definition of the glycosidic conformational ranges Newman projections showing the three staggered conformations about the exocyciic C(4')-C(5') bond Sugar pucker of nucleosides (S and N-type sugars) Structure of 8,2 '-thioanhydroadenosine (3) Sugar pucker of 8,2'-thioaabydroadenosine (3) Structure of adenosine-2 ''3 '-carbonate (9) X 13 Structure of 23'-anhydrouridine (6) 23 Physiologicai effects of ATP in PC 12 cells 27 Structure of 8-mercaptoadenosine (8) 29 Structure of adenosine-2',3'-carbonate (9) 30 Newman projection dong the C(l ')C(2')bond mis of 8-bromoadenosine 46 -2',3'-carbonate (2) Separation of nucleoside phosphates on DEAE-Sephadex eluted with 48 TEAB (0-700 mM) 31P-NMR specm of nucleoside friphosphate (peak TV) The course of [3~-adenosineuptake into PC12 cek in the presence and absence of dipyridamole (0.1 mM) Adenosine transport in PC12 ceh in the presence of various nucleosides Accumulation of radioactive ['Hl-purines in PC12 ceb in the presence and absence of inhibitors of adenosine metabolism 58 Purine accumulation in PC12 ceik (96 of control) in the presence and absence of adenosine metaboikm inhibitors 60 Time course of adenosine uptake in PC12 cek in the presence and absence of inhibitors of adenosine metabolism Adenosine uptake in PC12 ceils in the presence of various naaval and synthetic nucleosides (30pM) Inhibition of adenosine uptake in PC 12 cells by adenosine-2'.
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