Design and synthesis of A3 adenosine receptor ligands, 3′-fluoro analogues of Cl-IB-MECA

Article abstract of DOI:10.1081/NCN-120022701

Synthesis of 3′-deoxy-3′-fluoro-N⁶-substituted adenosines as bioisosteres of Cl-IB-MECA and their binding affinities to A ₃ adenosine receptor are described.

Full text of DOI:10.1081/NCN-120022701

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Design and Synthesis of A3 Adenosine Receptor Ligands,
3′-Fluoro Analogues of Cl-IB-MECA
Hea Ok Kim a , Moo Hong Lim b , Jae Gyu Park c , Hyung Ryong Moon c , Kenneth A. Jacobson
d , Hee-Doo Kim e , Moon Woo Chun b & Lak Shin Jeong c f
a Division of Chemistry and Molecular Engineering, Seoul National University, Seoul, Korea
b College of Pharmacy, Seoul National University, Seoul, Korea
c College of Pharmacy, Ewha Womans University, Seoul, Korea
d Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney
Diseases, NIH, Bethesda, Maryland, USA
e College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
f Ewha Wowans University, College of Pharmacy, 11-1 Seodaemun-gu, Duehyun-dong,
120-750, Seoul, South Korea
Published online: 31 Aug 2006.
To cite this article: Hea Ok Kim , Moo Hong Lim , Jae Gyu Park , Hyung Ryong Moon , Kenneth A. Jacobson , Hee-Doo Kim ,
Moon Woo Chun & Lak Shin Jeong (2003) Design and Synthesis of A3 Adenosine Receptor Ligands, 3′-Fluoro Analogues of Cl-IB-
MECA, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 923-925, DOI: 10.1081/NCN-120022701
To link to this article: http://dx.doi.org/10.1081/NCN-120022701
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 923–925, 2003
Design and Synthesis of A3 Adenosine Receptor Ligands,
30-Fluoro Analogues of Cl-IB-MECA
Hea Ok Kim,1 Moo Hong Lim,2 Jae Gyu Park,3 Hyung Ryong Moon,3
Kenneth A. Jacobson,4 Hee-Doo Kim,5 Moon Woo Chun,2
and Lak Shin Jeong3,
*
1Division of Chemistry and Molecular Engineering and
2College of Pharmacy, Seoul National University, Seoul, Korea
3College of Pharmacy, Ewha Womans University, Seoul, Korea
4Laboratory of Bioorganic Chemistry, National Institute of Diabetes and
Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
5College of Pharmacy, Sookmyung Women’s University, Seoul, Korea
ABSTRACT
Synthesis of 30-deoxy-30-fluoro-N6-substituted adenosines as bioisosteres of
Cl-IB-MECA and their binding affinities to A3 adenosine receptor are described.
Key Words: A3 adenosine receptor; 30-Deoxy-30-fluoro-N6-substituted adeno-
sines.
From the structure-activity relationship study for N6- and 50-substituted adeno-
sine derivatives as agonists at rat A3 adenosine receptors,[1] 2-chloro-N6-(3-iodoben-
zyl)-adenosine-50-methylcarboxamide (Cl-IB-MECA) has been recognized to be one
of the most selective agonists (Ki ¼ 1.0 nM).[2] On the basis of its high binding affinity
*Correspondence: Lak Shin Jeong, Ewha Wowans University, College of Pharmacy, 11-1
Seodaemun-gu, Duehyun-dong, 120-750 Seoul, South Korea; Fax: +82 23 277 2851; E-mail:
lakjeong@ewha.ac.kr.
923
DOI: 10.1081/NCN-120022701
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

924
Kim et al.
Scheme 1. Reagents and conditions: (a) TsCl; (b) i. 80% AcOH, ii. NaOMe, MeOH;
(c) KHF2, NaF, 1,2-ethylene glycol, reflux; (d) TBSCl; (e) TsCl, pyridine; (f) NaOBz,
18-crown-6, DMSO, reflux; (g) BzCl; (h) Ac2O, AcOH, H2SO4; (i) TBSCI; (j) i. NaOMe,
ii. RuCl3, NalO4, MeCN=CCl4=H2O (1=1=1.5), iii. DCC, DMAP, MeOH; (k) i.
TBAF=AcOH, THF, ii. BzCl; (l) Ac2O, AcOH, H2SO4.
to adenosine A3 receptor, we wanted to determine whether 20- or 30-hydroxyl group
of 2-Cl-IB-MECA is compatible with bioisosteric fluorine for the binding affinity to
adenosine A3 receptor. Herein, we report the synthesis of the new ligands, 30-fluoro
analogues to substitute the 30-hydroxyl group of Cl-IB-MECA with bioisosteric
fluorine and their evaluation for binding affinity to the adenosine A3 receptor.
For the synthesis of 30-fluoro analogues of Cl-IB-MECA, the glycosyl donors 8
and 14 were first synthesized according to Sch. 1, using regioselective opening[3] of 4a
and 4b with fluoride anion as a key step.The synthesized glycosyl donors 8 and 14
were condensed with silylated 2,6-dichloropurine and silylated 2-chloro-N6-(3-iodo-
benzyl) adenine and then transformed to the final nucleosides 17 and 19 according to
Schs. 2 and 3, respectively.
The final nucleosides 17 and 19 were evaluated in radioligand binding assays[4–6]
for affinity at rat brain A1 and A2A and human A3 adenosine receptors. Compared to
the high binding affinity (Ki ¼ 1.0 nM) of Cl-IB-MECA to the A3 adenosine receptor,
binding affinities (Ki ¼ 75 nM and 406 nM) of compounds 17 and 19 to A3 receptor
Scheme 2. Reagents and conditions: (a) silylated 2,6-dichloropurine, TMSOTf; (b) 3-iodo-
benzylamine hydrochloride, EtOH; (c) NaOMe, MeOH.

30-Fluoro Analogues of Cl-IB-MECA
925
Scheme 3. Reagents and conditions: (a) silylated 2-chloro-N6-(3-iodobenzyl)adenine,
TMSOTf; (b) 2 M MeNH2.
were remarkably decreased, but no binding affinity (Ki > 10,000 nM) to A2A recep-
tor and similar binding affinity to A1 receptor were observed for both compounds.
This biological result indicates that the bioisosteric fluorine can not substitute for
the 30-hydroxyl group in binding to A3 and A2A adenosine receptors, especially to
A2A receptor, but has little effect on binding to A1 receptor.
ACKNOWLEDGMENT
This work was supported by Korea Research Foundation Grant (KRF-2000-
042-F00121).
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