Design and synthesis of A3 adenosine receptor ligands, 2′-fluoro analogues of Cl-IB-MECA

Article abstract of DOI:10.1081/NCN-120022687

Synthesis of 2′-deoxy-2′-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-120022687

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Design and Synthesis of A3 Adenosine Receptor Ligands,
2′-Fluoro Analogues of Cl-IB-MECA
Hea Ok Kim a , Jae Gyu Park b , Hyung Ryong Moon b , Prashantha Gunaga b , Moo Hong Lim c
, Moon Woo Chun c , Kenneth A. Jacobson d , Hee-Doo Kim e & Lak Shin Jeong b g
a Division of Chemistry and Molecular Engineering , Seoul National University , Seoul, Korea
b College of Pharmacy, Ewha Womans University , Seoul, Korea
c College of Pharmacy, Seoul National University , Seoul, Korea
d Laboratory of Bioorganic Chemistry, National Institutes of Diabetes, and Digestive and
Kidney Diseases, NIH , Bethesda, Maryland, USA
e College of Pharmacy, Sookmyung Women's University , Seoul, Korea
f Division of Chemistry and Molecular Engineering , Seoul National University , 151742,
Seoul, Korea
g Ewha Womans University, College of Pharmacy , 11-1 Seodaemun-gu, Daehyun-dong,
120-750, Seoul, South Korea
Published online: 31 Aug 2006.
To cite this article: Hea Ok Kim , Jae Gyu Park , Hyung Ryong Moon , Prashantha Gunaga , Moo Hong Lim , Moon Woo Chun ,
Kenneth A. Jacobson , Hee-Doo Kim & Lak Shin Jeong (2003) Design and Synthesis of A3 Adenosine Receptor Ligands, 2′-Fluoro
Analogues of Cl-IB-MECA, Nucleosides, Nucleotides and Nucleic Acids, 22:5-8, 927-930, DOI: 10.1081/NCN-120022687
To link to this article: http://dx.doi.org/10.1081/NCN-120022687
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS
Vol. 22, Nos. 5–8, pp. 927–930, 2003
Design and Synthesis of A3 Adenosine Receptor Ligands,
20-Fluoro Analogues of Cl-IB-MECA
Hea Ok Kim,1 Jae Gyu Park,2 Hyung Ryong Moon,2
Prashantha Gunaga,2 Moo Hong Lim,3 Moon Woo Chun,3
Kenneth A. Jacobson,4 Hee-Doo Kim,5
and Lak Shin Jeong2,
*
1Division of Chemistry and Molecular Engineering,
Seoul National University, Seoul, Korea
2College of Pharmacy, Ewha Womans University, Seoul, Korea
3College of Pharmacy, Seoul National University, Seoul, Korea
4Laboratory of Bioorganic Chemistry, National Institutes of Diabetes,
and Digestive and Kidney Diseases, NIH, Bethesda,
Maryland, USA
5College of Pharmacy, Sookmyung Women’s University,
Seoul, Korea
ABSTRACT
Synthesis of 20-deoxy-20-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; 20-Deoxy-20-fluoro-N6-substituted.
*Correspondence: Lak Shin Jeong, Ewha Womans University, College of Pharmacy, 11-1
Seodaemun-gu, Daehyun-dong, 120-750 Seoul, South Korea; Fax: +82 23 277 2851; E-mail:
lakjeong@ewha.ac.kr.
927
DOI: 10.1081/NCN-120022687
Copyright # 2003 by Marcel Dekker, Inc.
1525-7770 (Print); 1532-2335 (Online)
www.dekker.com

928
Kim et al.

20-Fluoro Analogues of Cl-IB-MECA
929
Since adenosine A3 receptor[1] was cloned from rat brain, a number of com-
pounds have been synthesized and evaluated for their binding affinity to this recep-
tor. Among these, 2-chloro-N6-(3-iodobenzyl)-adenosine-50-methylcarboxamide
(Cl-IB-MECA)[2] has been found to be one of the most selective agonists (Ki ¼
1.0 nM) for rat adenosine A3 receptor. Based on this high binding affinity of Cl-
IB-MECA to adenosine A3 receptor, we wanted to synthesize the 20-deoxy-20-fluoro-
adenosine analogues to determine if the 20-hydroxyl group of Cl-IB-MECA is
compatible with fluorine atom, based on the bioisosteric rationale and to compare
their binding affinities with those of Cl-IB-MECA. In the present paper, we report
the synthesis of the new ligands, 20-deoxy-20-fluoroadenosine analogues from d-
arabinose and their binding affinities to different adenosine receptors.
The synthesis of the 20-deoxy-20-fluoroadenosine analogues, 1a–1c of Cl-IB-
MECA started from d-arabinose as shown in Sch. 1. d-Arabinose was converted
to 2-deoxy-2-fluororibose derivative 2 according to the known procedure.[3] Com-
pound 2 was converted to the glycosyl donor 3 by acetylation, acid-catalyzed hydro-
lysis and acetylation. Condensation of 3 with silylated 2,6-dichloropurine in the
presence of SnCl4 afforded the desired nucleoside 4 which was converted to the final
deprotected congeners 1a and 1b, by treating with 3-iodobenzyl amine followed by
sodium methoxide or with methylamine, respectively. For the synthesis of 40-carbox-
amide derivative 1c, compound 2 was successively treated with TBDPSCl and ben-
zoyl chloride to give 5. Silyl deprotection of 5 followed by conversion of the resulting
alcohol to the methyl ester produced 6. Treatment of 6 with 80% trifluoroacetic acid
followed by acetylation produced another glycosyl donor 7, which was converted to
the final 4-carboxamide 1c using the similar method used above.
The final nucleosides 1a–1c were evaluated in radioligand binding assays[4–6] for
affinity at rat brain A1 and A2A and human A3 adenosine receptors. Compounds 1a–1c
did not exhibit any binding affinity to human A3 receptor up to 1 mM of Ki unlike
high binding affinity (Ki ¼ 1.0 nM) of Cl-IB-MECA to A3 adenosine receptor, indi-
cating that 20-hydroxyl group of Cl-IB-MECA is essential for binding to the recep-
tor. Binding affinities of compounds 1a–1c to rat A1 and A2A receptors were also
remarkably decreased, emphasizing the importance of the 20-hydroxyl group to
these receptors. This biological result indicates that the bioisosteric fluorine can not
substitute for the 20-hydroxyl group in binding to either A1, A2A, or A3 adenosine
receptors.
ACKNOWLEDGMENT
This work was supported by Korea Research Foundation Grant (KRF-2000-
042-F00121).
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