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Cyclic Adenosine Monophosphate : a Study of Four- and Five-Coordinated Phosphorus Compounds, Modelling the Activated State of Camp

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Cyclic Adenosine Monophosphate : a Study of Four- and Five-Coordinated Phosphorus Compounds, Modelling the Activated State of Camp On the mechanism of action of 3',5'-cyclic adenosine monophosphate : a study of four- and five-coordinated phosphorus compounds, modelling the activated state of cAMP Citation for published version (APA): Broeders, N. L. H. L. (1993). On the mechanism of action of 3',5'-cyclic adenosine monophosphate : a study of four- and five-coordinated phosphorus compounds, modelling the activated state of cAMP. Technische Universiteit Eindhoven. https://doi.org/10.6100/IR398989 DOI: 10.6100/IR398989 Document status and date: Published: 01/01/1993 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication 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. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 01. Oct. 2021 ON THE MECHANISM OF ACTION OF 3' ,5'-CYCLIC ADENOSINE MONOPHOSPHATE A Study of Foor- and Five-coordinated Phosphorus Compounds, Modelling the Activated State of cAMP PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven, op gezag van de Rector Magnificus, prof. dr. J.H. van Lint, voor een commissie aangewezen door het College van Dek:anen in het openbaar te verdedigen op woensdag 30 juni 1993 om 14.00 uur door NICOLAAS LAMBERTUS HENDRINUS LAURENTJUS BROEDERS geboren te VVagenberg do <ol. w ol ll<ll h · .·,, ·ol diU·Ih<IU o•l 'I ru·lllnuod Dit proefschrift is goedgekeurd door de promotoren: prof. dr. E. W. Mcijer en prof. dr. E.M. Meîjer Copromotor: dr. ir. L.ll. Kook CIP-GEGF.VENS KONINKLIJKE Bl8LIOTHEEK, DEN HAAG Broeders, Nicolaas Lambertus Hendrinus Laurentius On the rnecl1<1nism of action of ~',5'-cyclic adenosine monophosphate: a study of four- and five-coordinated phosphorus cornpounds, modelling thc activaled state of cAMP I Nicolaas Lambertus Hendrinus Lu1rcntius Broeders. -Eindhoven: Eindhoven University of Technology Proefsçhrift Eindhoven. - Met lit. opg. - Met s<•menvattîng in het Nederlands. ISBN 90-386-0222-7 Trefw.: fosfor. Ter :naeedäclitenis aan mijn Ouders Yoor .Jl.gnès Contents Contents 1 General lotroductlon 9 1.1 Inttoduction 9 l. 2 cAMP Analogues 14 l. 3 Role of Pbosphorus in !he Mechanism of Action of cAMP 15 1.4 A Closer Look at Five-roordinated Phosphorus 17 1.5 Aim and Outline of !he Thesis 21 References and Notes 23 2 A 400- and 600-MHz 1H NMR Study on tbe Orieotation and Confonnation of l.be 3' ,5'-Dioxaphosphorinane Ring in Nucleoside 3' ,S'-Cydic pV-TBP Systems 27 2.1 1nttoduction 28 2.2 Results and Discussion 30 2.2.1 Prepatation of Compounds 2-9 30 2.2.2 Conformational Analysis 32 2.2.2.1 Location of !he 3',5'-Dioxaphosphorinane Ring in pV.mp 2 and 3 32 2.2.2.2 Conformation of !he 2' -Deoxyribose Ring 37 2.2.2.3 Conformation of the 3' ,5' -Dioxaphosphorinane Ring in pV_ TBP 2 and 3 39 2.3 Conclusions 44 2.4 Experimental 45 2.4.1 Material and Methods 45 2.4.2 Synthesis 45 References and Notes 53 3 A ' 1P NMR Stereocbemical and Kinetic Study of the Alkaline Hydrolysis ot cis-Nucleoside 3' ,5'-Cyclic Aryl [180]Mon<>­ phosphates and Uniabelled Analogues 57 3. I Introduetion 58 3.2 Results and Discussion 60 3.2.1 Synthesis 60 3.2.2 Hydralysis of 3a-c 61 Conlenis 3.2.3 Hydrolysis of 180-Labelled 3',5'-cyelic Phosphate Triesters 4a-<: 63 3.2.3.1 Stereochemical Analysi> of lhe 3' ,5' -Cyclie Methyl Phosphate Triesters 67 3.2.3.2 Stereochemical Analysis of lhe Acyelîc 3'· and 5'-Methyl Acyl Phosphate Triesters 69 3.3 Interprelation and Conclusions 73 3.4 Experimental 80 3.4 .I Matenals and Chmmatography 80 3.4.2 NMR Measurements 81 3.4.3 UV/Visible Spectroscopy 81 · 3.4.4 Synlhesis 81 3.4.5 Hydrolysis 87 3.4.5.1 General Procedure for lhe Hydrolysis of 3a, 3b and 3e 87 3.4.5.2 Hydralysis of cis-Thymidine 3' ,5'-Cyclic Phenyl [ 180]Monophosphate (4a) and Melhylation of lhe Produets 88 3.4.5.3 Hydrolysis of cis-Thymidine 3',5'-Cyclic p-Nitrophenyl [ 180]Monophosphate (4b) and Methylation of lhe ProduelS 89 3.4.5.4 Hydrolysis of 2'-0-Methyl-cis-Adenosine 3' ,5'-Cyclic Phenyl e•o]Monophosph,ate (4c) and Methylation of lhe ProduelS 90 Appendix 91 References and Notes 93 4 2'-0-Metbyl-Cis-Adenosine 3',$'-Cyclic Metbyl Monopbosphate, a New Model System for . cAMP. Aspects of Structure and Reactivity 97 4, I Introduetion 98 4.2 Results and Discussion 99 4.2.1 Synlhesis 99 4.2.2 Crystal Struclure 100 4.2.2.1 Conformation of lhe Ribose Ring 100 4.2.2.2 Conformation of lbe 3' ,5'-Dioxaphosphorinane Ring 106 4.2.2.3 Geometry and Orientation of lhe Base 109 4.2.2.4 Molecular Paclting and Hydragen Bonding 109 4.2.3 Conformation in Solution lil Conlenis 4.2.3.1 Conformation of the Ribose Ring 111 4.2.3.2 Conformation of the 3' ,5'-Dioxaphosphorinane Ring 112 4.2.4 Hydrolysis of Cis-4 113 4.3 Conclusions 114 4.4 Experimental 117 4.4.1 Matcrials and Chromatography 117 4.4.2 NMR Spectroscopy 118 4.4.3 Synthesis 118 4.4.4 Hydrolysis of Cis-4 ll9 4.4.5 Crystal1ographic Measurements and Structure Resolution 119 References and Notes 121 Summary 125 Samenvatting 128 Curri<ulum Vilae 131 1 General Introduetion 1.1 Introduetion The study of pbosphorus compounds started in 1669, as Hennig Brand, a German alchemist from Hamburg, !ried 10 malre gold out of putrefied urine. Brand discovered a substance that is known as white phosphorus: a white, crystalline solid tllat glows in tlle dark and ignites sponllll1eously in air just above room temperature. Later on, white phosphorus attracted considerable attention because of its utility in warfare. White phosphorus bums rapidly in air 10 form phosphoric oxide (P40 10). In the atmosphere, P40 10 appoars as a dense white smoke, and it was discovered during World War I that the obscuring power of this smoke per kg of phosphorus was greater than of any smoke-generating chemieal then known. The number of applications of phosphorus compounds has increased enormously since the days of World War I. For example, the dîscovery of Schrader and others that some organîc phosphates display marked toxic and insecticidal proporties, has created a whole new industry. 1 Today, we encounter phosphorus compounds al most anywhere in our everyday life. A few examples may help to illustrate Ibis. Phosphates occur in oor cleaning agents and detergents, phosphates are used in water treatment, and phosphates are abundant in our food (for exarnple, a cola drink is actually a llavoured, carhonated, sweetened, diluted solution of phosphoric acid). Other more exotic phosphorus compounds occur in fertilizers, pharmaceutieals, and as "llame retardants" in • 9 10 General Introductloo polymerie materials. This lhesis deals wilh aspecl.s of ,lhe role of phosphorus compounds in lhe functioning of living cells, A living cell functions lhrough lhe action of many phosphorus containing compounds: lhe biophosphates, Tbe most important memhers of this class are DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), bolh carriers of lhe genetic code. In DNA and RNA, phosphate groups are found in lhe backbene of lhe well-known spiral-staircase structure. Tbe essential building blocks, called lhe nucleotides, each consist of a nitrogen-containing base, a live-carbon sugar (for DNA, deoxyribose) and phosphoric acid. Four different nitrogen­ containing bases are present in a DNA molecule: lhe two purines adenine (A) and guanine (G), and lhe two pyrimidines thymine (11 and cytosine (C). In lhe double helix, A is coupled to T via two hydrogen bonds and G is coupled to C via lhree hydrogen bonds. Tbe phosphate groups, which are located on lhe periphery of lhe double helix, are of essential importance in DNA-enzyme interactions. Besides, lhe phosphates play a key role in salt-induced conformational changes of DNA, such as: a righlhanded B-DNA helix changing towards a lefthanded Z.DNA helix occuring in d(CG· · ·CG)2 duplexes. Other essential biophosphates are ATP (adenosine triphosphate), which serves as an energy carrier, and 3' ,5' ..:yclic adenosine monophosphate (cAMP) which mediatos lhe action of many honnones and reguiatos important activities in almost every living cell.
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