Synthesis of 3′-ureidoadenosine analogues and their binding affinity to the A3 adenosine receptor

Article abstract of DOI:10.1081/NCN-200060079

Novel 3′-ureidoadenosine analogues were synthesized from 1,2:5,6-di-0-isopropylidene-D-glucose in order to lead to stronger hydrogen bonding at the A₃ adenosine receptor than the corresponding 3-aminoadenosine derivatives. However, all synthesi

Full text of DOI:10.1081/NCN-200060079

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SYNTHESIS OF 3′-UREIDOADENOSINE ANALOGUES
AND THEIR BINDING AFFINITY TO THE A3 ADENOSINE
RECEPTOR
Moon Woo Chun a , Hyouk Woo Lee a , Ae Yil Kim b , Myong Jung Kim a , Hea Ok Kim c , Zhan-
Guo Gao c , Kenneth A. Jacobson c & Lak Shin Jeong b
a Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National
University , Seoul, Korea
b Laboratory of Medicinal Chemistry , College of Pharmacy, Ewha Womans University , Seoul,
Korea
c Laboratory of Bioorganic Chemistry, Molecular Recognition Section , National Institute
of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda,
Maryland, USA
Published online: 28 Jul 2006.
To cite this article: Moon Woo Chun , Hyouk Woo Lee , Ae Yil Kim , Myong Jung Kim , Hea Ok Kim , Zhan-Guo Gao , Kenneth
A. Jacobson & Lak Shin Jeong (2005) SYNTHESIS OF 3′-UREIDOADENOSINE ANALOGUES AND THEIR BINDING AFFINITY TO THE A3
ADENOSINE RECEPTOR, Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 1119-1121, DOI: 10.1081/NCN-200060079
To link to this article: http://dx.doi.org/10.1081/NCN-200060079
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):1119–1121, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060079
SYNTHESIS OF 3’-UREIDOADENOSINE ANALOGUES AND THEIR
BINDING AFFINITY TO THE A3 ADENOSINE RECEPTOR
5
Moon Woo Chun and Hyouk Woo Lee
Research Institute of Pharmaceutical
Sciences, College of Pharmacy, Seoul National University, Seoul, Korea
5
Ae Yil Kim
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans
University, Seoul, Korea
5
Myong Jung Kim
Research Institute of Pharmaceutical Sciences, College of Pharmacy,
Seoul National University, Seoul, Korea
5
Hea Ok Kim, Zhan-Guo Gao, and Kenneth A. Jacobson
Laboratory of Bioorganic
Chemistry, Molecular Recognition Section, National Institute of Diabetes and Digestive and
Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
5
Lak Shin Jeong
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha
Womans University, Seoul, Korea
5
Novel 3’-ureidoadenosine analogues were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose in
order to lead to stronger hydrogen bonding at the A3 adenosine receptor than the corresponding 3’-
aminoadenosine derivatives. However, all synthesized 3’-ureidoadenosine analogues have lost their
binding affinities to the all subtypes of adenosine receptors, indicating that bulky 3’-urea moiety led to
conformational distortion.
INTRODUCTION
Among many N6-and/or 2-substituted adenosine derivatives with A3 adenosine
receptor agonistic activity, N6-(3-iodobenzyl)-5’-N-methylcarbamoyladenosine
(IB-MECA) and 2-chloro-N6-(3-iodobenzyl)-5’-N-methylcarbamoyladenosine (Cl-
IB-MECA) were found to be highly selective full agonists with high binding
affinities (Ki = 1.8 0.7 nM, 1.4 0.3 nM, respectively) at the human A3
adenosine receptor.[1,2] On the basis of high binding affinity of Cl-IB-MECA, we
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 Lak Shin Jeong, Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea.
1119
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1120
M. W. Chun et al.
have recently reported the role of 3’-hydroxyl group of Cl-IB-MECA as a hydrogen
bonding donor, not a hydrogen bonding acceptor by comparing its binding affinity
with 3’-fluoro analogue of Cl-IB-MECA.[3] More recently, 3’-aminoadenosine
analogues[4] exhibited potent agonistic activity at the human A3 adenosine receptor,
indicating that 3’-amino group served as a hydrogen bonding donor at the binding
site of the human A3 adenosine receptor.
Thus, as our continuing efforts to search for potent and selective A3 adenosine
receptor agonists, it was of great interest to design 3’-ureidoadenosine analogues
since 3’-ureido moiety may form stronger hydrogen bond in the binding site than
the corresponding 3’-amino-or 3’-hydroxy-substituted nucleosides.
RESULTS AND DISCUSSION
The target nucleosides 8a,b and 9a,b were synthesized from 1,2:5,6-di-O-
isopropylidene-D-glucose as shown in Scheme 1.
Treatment of 1,2:5,6-di-O-isopropylidene-D-glucose (1) with triflic anhydride in
pyridine followed by treating with sodium azide in DMF produced azido sugar 2.
Selective hydrolysis of 2 with 75% aqueous acetic acid followed by successive
treatments with NaIO4 and NaBH4 afforded a 4-hydroxylmethyl derivative, which
was acetylated to give 3. Hydrolysis of 3 using 85% formic acid followed by
acetylation of the resulting diol with acetic anhydride in pyridine afforded the key
intermediate 4. The glycosyl donor 4 was condensed with silylated 6-chloropurine
in the presence of TMSOTf as a Lewis acid catalyst afforded the protected
nucleoside 5. Compound 5 was treated with methylamine and 3-iodobenzylamine
to give the N6-substituted nucleosides, 6a and 6b, respectively. The acetyl
protecting groups of 12a and 12b were removed and protected again as
TBS ethers 6a and 6b, respectively, because of the facile migration of a 2’-acetyl
group to the 3’-ureido group. Reduction of azido group of 6a and 6b with
SCHEME 1

M. W. Chun et al.
1121
triphenylphosphine and ammonium hydroxide in aqueous solution yielded 3’-
amino derivatives, 7a and 7b, respectively. For the introduction of urea moiety to
the 3’-position, the amino derivatives, 7a and 7b was treated with chloroacetyl
isocyanate in DMF followed by treating with sodium methoxide to give the 3’-ureido
derivatives, 8a and 8b, respectively after desilylation with tetra-n-butylammonium
fluoride. The 5’-uronamide derivatives 9a and 9b were synthesized from 1,2:5,6-di-
O-isopropylidene-D-glucose (1), according to our previous procedure.[5]
Binding affinity of the synthesized nucleosides, 8a,b and 9a,b were measured
using radioligand binding assays. Unfortunately, all tested compounds were totally
devoid of their binding affinities at all subtypes of adenosine receptors, indicating
that 3’-urea moiety might cause steric repulsion at the binding site of the receptor,
leading to conformational distortion, although it might potentially serve as stronger
hydrogen bonding donor than hydroxyl or amino group.
In summary, novel 3’-ureidoadenosine derivatives were synthesized from
1,2:5,6-di-O-ispropylidene-D-glucose. The key 3’-urea moiety was introduced from
reacting 3’-amino derivative with chloroacetylurea followed by treating with sodium
methoxide. Although 3’-ureidoadenosine derivatives did not exhibit potent A3
adenosine receptor agonistic activity, our results will give valuable information
about the identification of the binding site of the A3 adenosine receptor.
REFERENCES
1. Gao, Z.-G.; Blaustein, J.B.; Gross, A.S.; Melman, N.; Jacobson, K.A. N6-Substituted adenosine derivatives:
selectivity, efficacy, and species differences at A3 adenosine receptors. Biochem. Pharmacol. 2003, 65(10),
1675–1684.
2. Kim, H.O.; Ji, X.-d.; Siddiqi, S.M.; Olah, M.E.; Stiles, G.L.; Jacobson, K.A. 2-substitution of N6-
benzyladenosine-5’-uronamides enhances selectivity for A3 receptors. J. Med. Chem. 1994, 37(21), 3614–3621.
3. Lim, M.H.; Kim, H.O.; Moon, H.R.; Lee, S.J.; Chun, M.W.; Gao, Z.-G.; Melman, N.; Jacobson, K.A.; Kim,
J.H.; Jeong, L.S. Synthesis and binding affinity of 3’-fluoro analogues of Cl-IB-MECA as adenosine A3 receptor
ligands. Bioorg. Med. Chem. Lett. 2003, 13(5), 817–820.
4. DeNinno, M.P.; Masamune, H.; Chenard, L.K.; DiRico, K.; Eller, C.; Etienne, J.B.; Tickner, J.E.; Kennedy,
S.P.; Knight, D.R.; Kong, J.; Oleynek, J.J.; Tracey, W.R.; Hill, R.J. 3’-aminoadenosine-5’-uronamides: discovery
of the first highly selective agonist at the human adenosine A3 receptor. J. Med. Chem. 2003, 46(3), 353–355.
5. Jeong, L.S.; Kim, M.J.; Kim, H.O.; Gao, Z.-G.; Kim, S.-K.; Jacobson, K.A.; Chun, M.W. Design and synthesis
of 3’-ureidoadenosine-5’-uronamides: effects of the 3’-ureido group on binding to the A3 adenosine receptor.
Bioorg. Med. Chem. Lett. 2004, 14(19), 4851–4854.