D-4′-thioadenosine derivatives as highly potent and selective agonists at the human A3 adenosine receptor

Article abstract of DOI:10.1081/NCN-200061827

4′-Thionucleoside derivatives as potent and selective A₃ adenosine receptor agonists were synthesized, starting from D-gulono-γ- lactone via D-thioribosyl acetate as a key intermediate, among which the 2· chloro-N⁶-methyladenosine-5′

Full text of DOI:10.1081/NCN-200061827

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D-4′-THIOADENOSINE DERIVATIVES AS HIGHLY
POTENT AND SELECTIVE AGONISTS AT THE HUMAN A3
ADENOSINE RECEPTOR
Hyouk Woo Lee a , Dae Hong Shin b , Ji Young Jung b , Hea Ok Kim c , Moon Woo Chun a , N.
Melman c , Z.-G. Gao c , Kenneth A. Jacobson c & Lak Shin Jeong b
a Laboratory of Medicinal Chemistry , College of Pharmacy, Ewha Womans University , Seoul,
Korea
b Molecular Recognition Section, Laboratory of Bioorganic Chemistry , NIDDK, NIH ,
Bethesda, Maryland, USA
c College of Pharmacy, Seoul National University , Seoul, Korea
Published online: 28 Jul 2006.
To cite this article: Hyouk Woo Lee , Dae Hong Shin , Ji Young Jung , Hea Ok Kim , Moon Woo Chun , N. Melman , Z.-G.
Gao , Kenneth A. Jacobson & Lak Shin Jeong (2005) D-4′-THIOADENOSINE DERIVATIVES AS HIGHLY POTENT AND SELECTIVE
AGONISTS AT THE HUMAN A3 ADENOSINE RECEPTOR, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 607-609, DOI:
10.1081/NCN-200061827
To link to this article: http://dx.doi.org/10.1081/NCN-200061827
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5--7):607–609, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200061827
D-4’-THIOADENOSINE DERIVATIVES AS HIGHLY POTENT AND
SELECTIVE AGONISTS AT THE HUMAN A3 ADENOSINE RECEPTOR
5
Hyouk Woo Lee
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha
Womans University, Seoul, Korea
5
Dae Hong Shin and Ji Young Jeong
Molecular Recognition Section, Laboratory of
Bioorganic Chemistry, NIDDK, NIH, Bethesda, Maryland, USA
5
Hea Ok Kim
College of Pharmacy, Seoul National University, Seoul, Korea
5
Moon Woo Chun
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha
Womans University, Seoul, Korea
5
N. Melman, Z.-G. Gao, and Kenneth A. Jacobson
College of Pharmacy, Seoul
National University, Seoul, Korea
5
Lak Shin Jeong
Molecular Recognition Section, Laboratory of Bioorganic Chemistry,
NIDDK, NIH, Bethesda, Maryland, USA
5
4’-Thionucleoside derivatives as potent and selective A3 adenosine receptor agonists were synthesized,
starting from D-gulono-g-lactone via D-thioribosyl acetate as a key intermediate, among which the 2-
chloro-N6-methyladenosine-5’-methyluronamide showed the most potent and selective binding affinity
(Ki = 0.28
0.09 nM) at the human A3 adenosine receptor.
INTRODUCTION
A number of ligands have been synthesized and tested for binding affinity at
the A3 versus A1 and A2A receptors. Among these ligands, IB-MECA (1) was found
to be a highly potent rat A3 agonist (Ki=1.1 nM), which is 50-fold selective for rat
brain A3 versus either A1 or A2 receptors.[1] Introduction of chlorine at the 2-
position of IB-MECA, resulting in the formation of Cl-IB-MECA (2),[1,2]
dramatically increased binding affinity and selectivity (Figure 1).
This work was supported by the grant from the Korea Health R & D Project, Ministry of Health & Welfare,
Korea (03-PJ2-PG4-BD02-0001).
Address correspondence to Hyouk Woo Lee, Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea.
607
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608
H. W. Lee et al.
FIGURE 1 The rationale for the design of the desired 4’-thionucleosides.
It has been reported to display a Ki value of 0.33 nM and showed 2500- and
1400-fold rat A3 receptor selectivity versus A1 and A2A receptors, respectively.
Thus, on the basis of the high binding affinity and selectivity of Cl-IB-MECA on A3
adenosine receptors, we designed and synthesized the 4’-thionucleoside analogues,
3a--f of Cl-IB-MECA, since a sulfur atom is well known as a bioisostere of an
oxygen atom.
RESULTS AND DISCUSSION
The target nucleosides were synthesized, starting from D-gulono-g-lactone (4)
via D-thioribosyl acetate 5[3] as a key intermediate (Scheme 1). The glycosyl donor
5 was condensed with silylated 2,6-dichloropurine to give the protected nucleoside
6. Compound 6 was treated with ammonia, methylamine, and 3-iodobenzylamine
followed by removal of the protecting groups to give 2-chloro-4’-thioadenosine
(3a), 2-chloro-N6-methyl-4’-thioadenosine (3b), and N6-(3-iodobenzyl)-4-thioadeno-
sine (3c), respectively.
SCHEME 1 Reagentsa: a) silylated 2,6-dichloropurine, TMSOTf; b) RNH2; c) i. 80% AcOH; ii. NaOMe, MeOH;
d) 80% AcOH; e) TBSCI, DMF; f) NaOMe, MeOH; g) i. PDC, DMF, ii. K2CO3, MeI; h) 40% MeNH2, MeOH;
i) n-Bu4NF, THF.

H. W. Lee et al.
609
For the synthesis of 4’-uronamide derivatives 3d--e, treatment of 6 with
ammonia, methylamine, and 3-iodobenzylamine followed by removal of the
isopropylidene group, protection of the resulting diol to TBS ether, and final
removal of the benzoyl group afforded 4a--c, respectively. Oxidation of 4a--c
with PDC in DMF followed by methylation gave their corresponding methyl esters,
which were converted to the final 4’-uronamide derivatives 3d--e, respectively,
after the successive treatments of methyl amine and tetra-n-buylammonium fluoride.
All synthesized 4’-thionucleosides exhibited higher binding affinity to the
human A3 adenosine receptor than Cl-IB-MECA, among which the 2-chloro-N6-
methyladenosine-5’-methyluronamide showed the most potent binding affinity
(Ki =0.28 0.09 nM). It was selective for A3 vs rat A1 and rat A2A receptors by 700-
and 23,000-fold, respectively and for A3 vs. human A1 and human A2A receptors by
4,800- and 36,000-fold, respectively.
In summary, we have discovered ultrapotent and selective A3 adenosine
receptor agonist by the simple change of furanose to thiofuranose. These nucleo-
sides may be useful as pharmacological tools and also are of interest for the
development of therapeutic agents.
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benzyladenosine-5’-uronamides enhances selectivity for A3-adenosine receptors. J. Med. Chem. 1994, 37,
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