UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
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.
Summary y
SynthesisSynthesis and Biological Activity of New Nucleoside Analogs
asas Inhibitors of Adenosine Deaminase
Adenosinee deaminase catalyzes (ADA) the hydrolytic deamination of adenosine and 2'-deoxyadenosinee to form inosine or 2'-deoxyinosine and ammonia. Several studies show that measurementt of ADA concentration in pleural fluid is useful in the assessment of tuberculosis. Highh adenosine deaminase concentration in serum is found in typhoid fever, brucellosis, viral hepatitiss and acquired immunodeficiency syndrome (AIDS). A brief introduction about the history,, mechanism of action of ADA and importance of its inhibitors is presented in Chapterr 1.
Sincee 1-deazaadenosine is a good inhibitor for ADA Chapter 2 introduces the synthesis andd functionalization of this ring system. Purpose of this investigation was to determine the requirementss and limits for interaction of substituted 1-deazaadenosine derivatives with ADA. Duringg our investigations towards selective derivatization of 1-deazapurine we introduced the tetrabutylammoniumm nitrate/trifluoroacetic anhydride (TBAN/TFAA) system for the regioselectivee nitration of electron deficient and acid labile nucleosides. This easy to handle reagentt requires mild reaction conditions and shows high selectivity for nitration in the pyridine ring.. Nitration occurred at the a or P-position with respect to the pyridine nitrogen atom, dependingg on the substituents in the ring. Nitration of 6-substituted systems 1 produced a 2,6-disubstitutedd 1-deazapurine nucleosides 2.
rr N. TBAN/TFAA N N
-N'' 'M OCDCM
L
H
nb(Ac)
33 2 N N'T. ,
vv 'J nb(Ac)3 R== CI or N02 11 2Thee regioselectivity of the nitration using TBAN/TFAA could be influenced by introductionn of an electronwithdrawing substituent in the pyridine ring. The fact that an electronn withdrawing group facilitates the nitration excludes an electrophilic process. The resultingg new nitro substituted nucleosides were converted into a variety of deazaadenosine analogs. .
Summary Summary tïb(Ac)33 rib(Ac)3 ^^ TBANATFAA 02N . ^ . N
'' > —-
xx>
ii i-
o-Inn Chapter 3 substitution of C2 in the purine ring system is described. For the functionalizationn of this ring system TBAN/TFAA nitrating agent was used. This reagent selectivelyy nitrates C6 substituted purines at the 2-position. Thus 6-chloro-purine riboside triacetatee 5 was cleanly nitrated (DCM, 0 °C, 71%) and converted into nitro substituted adenosinee and inosine in a few simple steps. This nitration is limited to substrates without free NHH or OH substituents.
CII CI
N^Srtt TBANATFAA N^SrA
rib(Ac)33 rib(Ac)3
AA general approach to l-deaza-2-azapurines by a hetero Diels-Alder reaction is described in Chapterr 4. Reaction of sulfonamide protected 5-vinylimidazole 7 with 4-phenyl-l,2,4-triazoline-3,5-dionee in methanol gave the Diels-Alder adduct 8 in 85% yield. Deprotection of thee resulting A'-phenyltriazole derivatives was efficiently accomplished by ring opening with hydrazinee followed by heating in DMSO. The completely deprotected and aromatized purine analogg 9 was obtained directly from this one-pot reaction in 48% yield.
RR S02NMe2 H
NN - ^ \ ^ N
rr' rr'
Summary Summary
Thee results of enzyme inhibition studies on ADA, for compounds described in chapter 2, 3 and 4 aree presented in Chapter 5. The main interactions of N l and N3 in the purine ring and
1-deazapurinee ring system with the enzyme is shown in the following figure.
NH2 2
Glu-217-Or.00 I }i b o s e ; 'i b o s e O O
HH H Gly-1844 Gly-184
Inn general, our studies have shown that for a good inhibitor and/or substrate substituents which improvee the electron density on N3 in the purine ring as well as in the 1-deazapurine ring are beneficiall since the hydrogen bond between N3 and Gly-184 becomes stronger. A number of the modifiedd nucleosides synthesized and tested are shown in the following figure.
NH2 2
XX X
RR N 100 R=NO 111 R=OCH3, 12R=NHOH H -N N -N N ribose e NH? ? 02N N NH, , ^ KK H , N ^ ^ N ^ ~ " N ribosee n 2 M IN I N N ribose e 133 X=N 144 X=CH 15 5 NN H2N ^ N ^ N 02N - ^ N ^ Nribosee ribose ribose
166 17 1 8 X = N 199 X= CH
Thee effect of electron withdrawing and donating substituents in adenosine derivatives 10 to 12 andd 1-deazaadenosine derivatives 14 to 17 was studies. In the purine and 1-deazapurine series thee effect of a nitro group on the ADA catalyzed conversion of 18 and 19 to transition state structuress was studied.
