UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
Synthesis and Biological Activity of New Nucleoside Analogs as Inhibitors of
Adenosine Deaminase.
Deghati, P.Y.F.
Publication date
2000
Link to publication
Citation for published version (APA):
Deghati, P. Y. F. (2000). Synthesis and Biological Activity of New Nucleoside Analogs as
Inhibitors of Adenosine Deaminase. Shaker Publishing BV.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)
and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open
content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please
let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material
inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter
to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You
will be contacted as soon as possible.
ChapterChapter 1: Introduction 5
1.11 Adenosine deaminase 5 1.22 Immunodeficiency diseases caused by ADA deficiency 7
1.33 Activation of drugs by ADA 8
1.44 ADA inhibition 8 1.4.11 Inhibition of ADA in cancer cells 9
1.4.22 ADA inhibitors as co-drugs 9
1.4.33 Protection of tissues 10 1.55 Crystals structure of ADA with different inhibitors 10
11 5.1 Atomic structure of ADA complexed with HDPR 10 1.5.22 Detailed structure of ADA complexed with DAA 11 1.66 An insight into action of ADA: The catalytic mechanism 12
1.77 Transition state structure 13 1.88 Classification of inhibitors for ADA 14
1.8.11 Ground state inhibitors 14 1.8.22 Transition state inhibitors 14 1.99 Previously reported ADA inhibitors 15
1.100 Outline of the thesis 16 1.111 References and notes. 17
ChapterChapter 2: 1 -Deazaadenosine Analogs 19
2.11 Introduction 19 2.22 Synthesis of the 1-deazapurine ring system 20
2.33 Functionalization of C6 in 1-deazapurines 21
2.3.11 Chlorination of C6 21 2.3.22 Nitration of C6 22 2.44 Functionalization of CI or C2 of 1-deazapurine ribosides 22
2.4.11 Nitration reactions 23 2.4.22 Nitration of pyridine and its N-oxide 24
2.4.33 Nitration of 1-deazapurine ribosides 24 2.4.44 Nitration of C6 substituted 1-deazapurine ribosides 26
2.55 Nitrated 1-deazapurines as precursors of new modified nucleosides 27
2.5.22 2-Amino-l-deazaadenosine 28 2.5.33 2-Nitro-l-deazapurine riboside 29 2.5.44 1-Nitro-l-deazapurine riboside 29 2.5.55 1 -Amino- 1-deazapurine riboside 30 2.5.66 2-Amino-l-deazapurine riboside 30 2.5.77 2-Nitro-I-deazainosine 31 2.5.88 2-Nitro-6-methoxy-l-deazapurine riboside 31 2.5.99 l-Nitro-2-chloro-l-deazapurine riboside 32 2.66 Structure determination 32 2.77 Conclusions 34 2.88 Acknowledgements 34 2.99 Experimental 34 2.100 References and notes 44
ChapterChapter 3: Adenosine Analogs 47
3.11 Introduction 47 3.22 Functionalization of C2 in the purine ring 48
3.2.11 2-Nitroadenosine 49 3.2.22 2-Nitroinosine 50 3.2.33 2-Nitropurine riboside 51
3.33 2-Nitrosoadenosine 53 3.3.11 Synthesis of 2-nitrosoadenosine 53
3.3.22 UV studies of nitroso compounds 56 3.3.33 1H NMR studies of 2-nitrosoadenosine 58 3.44 Functionalization of C2 in 2'-deoxyadenosine 59
3.55 Mechanism of the nitration 60 3.66 Structure determination by 1H NMR studies 63
3.77 "C NMR assignment of 2-nitroadenosine 64 3.88 Functionalization of the purine nucleoside at C6 66 3.99 Functionalization of purine riboside at Nl 67
3.100 Conclusions 68 3.111 Acknowledgements 69 3.122 Experimental 67
ChapterChapter 4: l-Deaza-2-azaadenosine Analogs 79 9
4.11 Introduction
4.22 Imidazo[4,5-c]pyridazine via a hetero Diels-Alder reaction 4.33 Preparation of the diene
4.44 Choice of dienophile
4.55 Removal of the protecting groups 4.66 Ribosylation of imidazo[4,5-c]pyridazine 4.77 Conclusions
4.88 Acknowledgments 4.99 Experimental 4.100 References and notes.
79 9 80 0 80 0 81 1 82 2 84 4 85 5 86 6 86 6 89 9
ChapterChapter 5: Enzyme Studies 91 1
5.11 Introduction
5.22 Mechanism of action of ADA
5.33 Role of zinc in the catalytic action of ADA 5.44 Rational and design of new inhibitors 5.55 General aspects of enzyme inhibition 5.5.11 Irreversible enzyme inhibitors 5.5.22 Reversible enzyme inhibitors
5.66 Assays for adenosine deaminase activity 5.6.11 ADA solutions
5.6.22 Km for adenosine and for 2-amino-6-chloropurine riboside 5.6.33 Test for substrate activity of modified nucleosides
5.6.44 Calculation of the Ki 5.77 Results and discussion
5.7.11 Adenosine analogs 5.7.22 2-Nitrosoadenosine 5.7.33 Purine analogs
5.7.44 Inosine analogs 5.7.55 1 -Deazaadenosine
5.7.66 I -Deazapurine riboside analogs 5.7.77 3-Deaza-6-azapurine riboside 91 1 92 2 92 2 93 3 94 4 94 4 95 5 97 7 98 8 98 8 99 9 99 9 100 0 101 1 103 3 103 3 105 5 105 5 107 7 109 9
