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2 Biologically Active Nucleoside Analogues with 5- Or 6- Membered Monocyclic Nucleobases 31 VU Research Portal Robust Applications in Time-Shared Distributed Systems Dobber, A.M. 2006 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Dobber, A. M. (2006). Robust Applications in Time-Shared Distributed Systems. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 25. Sep. 2021 Mureidomycin A and Dihydropyrimidine Nucleosides Exploring efficient multicomponent reactions and chemo‐enzymatic approaches Danielle J. Vugts © 2006, D. J. Vugts, Amsterdam Cover design: Anette Coppens VRIJE UNIVERSITEIT Mureidomycin A and Dihydropyrimidine Nucleosides Exploring efficient multicomponent reactions and chemo-enzymatic approaches ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Exacte Wetenschappen op vrijdag 15 december 2006 om 13.45 uur in het auditorium van de universiteit, De Boelelaan 1105 door Daniëlle Johanna Vugts geboren te Tilburg promotor: prof.dr. M.B. Groen copromotor: dr. R.V.A. Orru aan mijn ouders Table of Contents List of Abbreviation 9 Chapter 1 Mureidomycin A; a New Potential Antibiotic 13 Chapter 2 Biologically Active Nucleoside Analogues with 5- or 6- Membered Monocyclic Nucleobases 31 Chapter 3 Multicomponent Synthesis of Dihydropyrimidines 67 Chapter 4 Synthesis of Thiazines and Dihydropyrimidine-2-thiones 95 Chapter 5 A Mild Chemo-Enzymatic Oxidation-Hydrocyanation Protocol 115 Chapter 6 Synthetic Studies towards the 3’-Deoxyribose Moiety 131 Chapter 7 Synthetic Studies towards Mureidomycin A and Dihydropyrimidine Nucleosides 151 Summary and Outlook 169 Samenvatting 173 Dankwoord 177 Curriculum vitae 181 List of Publications 183 List of Abbreviations AICAR 5-aminoimidazole-4-carboxamide ribonucleoside AMBA 2-Amino-3-methylaminobutanoic acid ADP adenosine diphosphate AMP adenosine monophosphate ATP adenosine triphosphate BB building block BDV borna disease virus BH benzoyl hydrazide br broad BSA bis(trimethylsilyl)acetamide BVDU (E)-5-(2-Bromovinyl)-2’-deoxyuridine Cbz benzoyloxycarbonyl CC column chromatography CF continuous flow d doublet de diastereomeric excess DEE diethyl ether DHPM dihydropyrimidine DIPEA diisopropylethylamine DMAP dimethylaminopyridine DMP Dess–Martin periodinane DMSO dimethyl sulfoxide DSC differential scanning calorimetry EA ethyl acetate ee enantiomeric excess EI electron impact EICAR 5-ethynylimidazole-4-carboxamide ribonucleoside ED50 median effective dose equiv. equivalents FICAR 5-fluoro imidazole-4-carboxamide ribonucleoside FPV influenza virus A GC gas chromatography GMP guanosine monophosphate GTP guanosine triphosphate HbHNL Hevea Brasiliensis Hydroxy nitrile lyase HBV hepatitis B virus HIV human immunodeficiency virus HCV hepatitis C virus HCN hydrocyanic acid HMCV human cytomegalovirus HMDS hexamethyldisilazane HMPA hexamethylphosphoric acid HNL Hydroxynitrile lyase HPLC high-performance liquid chromatography 9 HRMS high-resolution mass spectra HSV herpes simplex virus HWE/aza-DA 4CR Horner-Wadsworth-Emmons/aza-Diels Alder four component reaction IC50 concentration at which cell growth is inhibited 50 % IMP inosine monophosphate IMPDH inosine monophosphate dehydrogenase IPCAR methyl-iodo-1-β-D-ribofuranosylpyrazole-3-carboxylate IPdR 5-Iodo-pyrimidin-2-one 2’-deoxyribose IPN infectious pancreatic necrosis IR infrared KU kilo unit LD50 concentration at which lethality is 50 % m medium MCR multi component reaction MIC minimal inhitory concentration MRD mureidomycin MS mass spectrum MTBE methyl t-butyl ether MVV maedi-visna virus MW microwave NAD nicotinamide adenine dinucleotide NaOCl sodium hypochlorite NDV newcastle disease virus NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PaHNL Prunus amygdalus Hydroxy nitrile lyase PCC pyridinium chlorochromate PDC pyridinium dichromate PE petroleum ether PG protecting group PsRV pseudorabies virus Rf retardation factor RVF rift valley fever RSV respiratory syncital virus Rt retention time s singlet/strong SAR structure-activity relationship spp species SVR sustained viral response t triplet TBS tert-butyldimethyl silyl TEMPO tetramethylpiperidinyloxy free radical THF tetrahydrofuran TLC thin layer chromatography TSAO 2’,5’-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl-3’-spiro-5’’- (4’’amino-1’’2’’-oxathiole-2’’,2’’-dioxide) 10 UDP uridine 5’-diphosphate UPA uridylpeptide antibiotic VEE venezuelan equine encephalitis VV vaccinia virus w weak YFV yellow fever virus ZMP AICAribotide 5-AZA-CdR 5-aza-2’-deoxycytidine 4CR four-component reaction 3-DC 3-deazacytidine 3-DU 3-deazauridine 11 1 Mureidomycin A a New Potential Antibiotic Over the last twenty years the incidence of life-threatening infections has increased while the number of immuno compromised persons has also increased. As a consequence the resistance of bacterial strains to current antibiotics like penicillins and vancomycin has become a major clinical threat. In the late eighties a family of antibiotics, the mureidomycins, has been discovered which act as antibacterial agent via inhibition of MraY, an essential enzyme in the peptidoglycan synthesis of bacteria. The mureidomycins have been investigated, but a clear inhibition mechanism has not been found. In this chapter a short summary will be given of what is known about the mureidomycins and the synthesis of their analogues. Chapter 1 1.1 Introduction Some seventy-five years ago antibiotics became available. When first discovered, antibiotics were thought to provide a miracle cure, and they literally were. Infections that were fatal before 1900 were tamed to mere inconveniences during the 20th century. However, the misuse, overprescription and abuse of antibiotics has allowed resistant strains of bacteria to develop and they once again threaten health and life.1 The first example of resistance to an antibiotic was observed in the early 1940s. Right after the introduction of penicillin, it was found that the Minimal Inhitory concentrations (MICs) for Staphylococcus aureus, which can cause severe food poisoning, increased.2 In the period of the 1980s and 1990s very potent broad-spectrum antibacterials were introduced. However, this led to concomitant increase in antibiotic resistance.3 The resistance of bacteria, fungi and yeasts against antibiotics can be described with three types of mechanisms: 4 a) Drug modification or inactivation b) Target modification c) Modified Cellular Uptake The development of resistance against antibiotics is a cause of serious concern and the search for new antibacterial agents is a hot topic. The problem adherent to this is that these new antibiotic agents will show also resistance leading to the question: when does the next generation of resistance factor emerge after new antibacterial agents have been introduced? 1.2 Targets for antibacterial drugs Almost all of the major antibiotics act against three primary processes in the pathogenic bacteria: protein biosynthesis, DNA replication and repair, and cell-wall biosynthesis (Figure 1.1).5-7 Protein biosynthesis offers many steps where antibiotics could disrupt the machinery; examples of these antibiotics are macrolides, tetracyclines, aminoglycosides and oxazolidinones.5 The only class of antibiotics in current use that blocks DNA replication and repair are the fluoroquinolones that exert their action by blocking the enzyme DNA gyrase and a cognate topoisomerase.8 Antibiotics directed against cell-wall biosynthesis include the β-lactam group of penicillins and cephalosporins as well as the glycopeptide antibiotic class, of which two members, vancomycin and teicoplanin, are approved for clinical use in humans.5 However, resistance has been reported against all of these antibiotics, which is a cause of concern. One of the possible solutions to overcome this problem is to find new biological targets e.g. in the cell-wall biosynthesis on which no antibiotic is currently acting. 14 Mureidomycin A; a New Potential Antibiotic Cell Wall Biosynthesis β−Lactams Vancomycin Teicoplanin Protein Biosynthesis Macrolides Tetracyclines Aminoglycosides Oxazolidinones DNA Replication and Repair Fluoroquinolones Figure 1.1 Bacterial targets of antibiotics This thesis focuses on the mureidomycins (MRDs), and this new class of antibiotics has been shown to disrupt the bacterial cell wall synthesis. The biosynthesis of peptidoglycan is a complex three-stage process. The first stage involves synthesis of N-acetylmuramyl- pentapeptide by enzymes located in the cytoplasm, or at the inner surface of the cytoplasmic membrane. First UDP-N-acetylmuramic acid is formed from UDP-
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