Synthesis of N6-Substituted 3′-ureidoadenosine derivatives as highly potent agonists at the mutant A3 adenosine receptor

Article abstract of DOI:10.1080/15257770701493161

Several N6-substituted 3′-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A3 adenosine receptor (AR) agonists. Among compounds tested, 3′-ureido-N6-(3-iodobenzyl)adenosine (2c) exhibited

Full text of DOI:10.1080/15257770701493161

Nucleosides, Nucleotides, and Nucleic Acids, 26:717–719, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701493161
SYNTHESIS OF N6-SUBSTITUTED 3ꢀ-UREIDOADENOSINE
DERIVATIVES AS HIGHLY POTENT AGONISTS AT THE MUTANT A3
ADENOSINE RECEPTOR
Lak Shin Jeong, Seung Ah Choe, Ae Yil Kim, and Hea Ok Kim
College of
2
Pharmacy, Ewha Womans University, Seoul, Korea
Zhan-Guo Gao and Kenneth A. Jacobson
Laboratory of Bioorganic Chemistry,
2
National Institute of Diabetes, and Digestive and Kidney Disease, NIH, Bethesda,
Maryland, USA
Moon Woo Chun
College of Pharmacy, Seoul National University, Seoul, Korea
2
Hyung Ryong Moon
College of Pharmacy, Pusan National University,
2
Busan, Korea
Several N 6 -substituted 3 ꢁ-ureidoadenosine derivatives were efficiently synthesized starting from
2
D-glucose for the development of H272E mutant A3 adenosine receptor (AR) agonists. Among com-
ꢁ
pounds tested, 3 -ureido-N 6 -(3-iodobenzyl)adenosine (2c) exhibited the highest binding affinity
(Ki = 0.22 µM) at the H272E mutant A3 AR without binding to the natural A3 AR.
Keywords Mutant A3 adenosine receptor; 3ꢁureidoadenosine derivatives; agonist;
electrostatic; neoligand; neoceptor
INTRODUCTION
Selective A3 adenosine receptor (AR) full agonists show high thera-
peutic potentials in the treatment of cardiac and cerebral ischemia[1] and
cancer[2] but, the ubiquitous presence of adenosine receptors throughout
the body hindered them from being developed as clinically useful agents.
Thus, Jacobson et al.[3] have demonstrated a re-engineered G protein-
coupled receptor, mutant A3 AR in which the His residue (H272) of natural
A3 AR, strongly hydrogen-bonded to the 3ꢁ-hydroxyl group of adenosine,[4]
was mutated to a negatively charged residue, Glu or Asp. This mutant A3AR
called neoceptor can recognize only a specifically designed A3 agonist, but
not the native A3 agonist.
This research was supported by a grant from Seoul R&BD Program, Korea (10541).
Address correspondence to Lak Shin Jeong, College of Pharmacy, Ewha Womans University, Seoul
120-750, Korea. E-mail: lakjeong@ewha.ac.kr
717

718
L. S. Jeong et al.
FIGURE 1 Rationale for the design of the desired nucleosides 2a–d.
Thus, for the purpose of developing optimal agonists at the mutant
A3AR, we modified the 3ꢁ-hydroxyl group of adenosine (1) to the 3ꢁ-ureido
group, because the 3ꢁ-ureido group is able to form highly favorable elec-
trostatic interaction with the Glu residue of H272E mutant A3 adenosine
SCHEME 1 Reagents and conditions: (a) NH4OH, 1,4-dioxane, rt or MeNH2, 1,4-dioxane, rt or 3-
iodobenzylamine-HCl or phenetylamine-HCl, Et3N, EtOH, 50◦C, then NaOMe, MeOH, rt; (b) TBSCl,
imidazole, DMF, rt; (c) Ph3P, NH4OH/H2O, THF, rt; (d) chloroacetyl isocyanate, DMF, 0◦C, then
NaOMe, MeOH, rt; (e) TBAF, THF, rt.

3ꢁ-Ureidoadenosine Derivatives as Mutant A3 Adenosine Receptor Agonists
719
receptor. Herein, we report the synthesis of 3ꢁ-ureidoadenosine derivatives
and their binding affinity at the mutant A3 adenosine receptor (Figure 1).
RESULTS AND DISCUSSION
Synthesis of the target nucleosides 2a–d started from the known inter-
mediate 3[5] which was derived from D-glucose, as depicted in Scheme 1.
Treatment of 3 with various appropriate amines followed by deacety-
lation with sodium methoxide gave the 3ꢁ-azido-N 6-substituted adenosine
derivatives 4a–d in high yields. Protection of two hydroxyl groups in 4a–d
with t-butyldimethylsilyl (TBS) group followed by catalytic hydrogenation
of azido group with triphenylphosphine in aqueous ammonium hydrox-
ide afforded the 3ꢁ-amino derivatives 5a–d, respectively. Conversion of 3ꢁ-
amino group into 3ꢁ-ureido group was accomplished by treating 5a–d with
chloroacetyl isocyanate followed by reacting with sodium methoxide to give
the 3ꢁ-ureido compounds 6a–d, respectively. Removal of TBS groups in 6a–d
with TBAF yielded the final nucleosides 2a–d, respectively.
Binding affinities of all synthesized 3ꢁ-ureido derivatives at the wild-type
A3 AR as well as H272E mutant A3 AR were measured using a radioligand
binding assay. All compounds did not show any significant binding affinities
to all subtypes of wild-type adenosine receptors. However, compound 2c had
no effect on the WT A3AR but bound to the H272E mutant receptor with a
Ki value of 0.22 µM.
In summary, we have synthesized the 3ꢁ-ureidoadenosine derivatives,
among which compound 2c formed a favorable electrostatic interaction
only at the H272E mutant A3 AR (neoceptor), not at the WT A3AR. This
selective ligand (neoligand)-neoceptor approach will expedite the develop-
ment of clinically useful organ-specific compounds.
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