Synthesis and biological activities of cyclic ADP-carbocyclic-ribose and its analogs

Article abstract of DOI:10.1081/NCN-100002554

An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was achieved. Treatment of N¹-carbocyclic-ribosyladenosine bisphosphate derivative 10 with AgNO₃ in the presence of molecular sieve

Full text of DOI:10.1081/NCN-100002554

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SYNTHESIS AND BIOLOGICAL ACTIVITIES OF CYCLIC
ADP-CARBOCYCLIC-RIBOSE AND ITS ANALOGS
Masayoshi Fukuoka a , Satoshi Shuto b , Noriaki Minakawa a , Yoshihito Ueno a & Akira
Matsuda a
a Graduate School of Pharmaceutical Sciences, Hokkaido University , Kita-12, Nishi-6,
Kita-ku, Sapporo, 060-0812, Japan
b Graduate School of Pharmaceutical Sciences, Hokkaido University , Kita-12, Nishi-6,
Kita-ku, Sapporo, 060-0812, Japan
Published online: 07 Feb 2007.
To cite this article: Masayoshi Fukuoka , Satoshi Shuto , Noriaki Minakawa , Yoshihito Ueno & Akira Matsuda (2001)
SYNTHESIS AND BIOLOGICAL ACTIVITIES OF CYCLIC ADP-CARBOCYCLIC-RIBOSE AND ITS ANALOGS, Nucleosides, Nucleotides
and Nucleic Acids, 20:4-7, 1355-1358, DOI: 10.1081/NCN-100002554
To link to this article: http://dx.doi.org/10.1081/NCN-100002554
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 20(4–7), 1355–1358 (2001)
SYNTHESIS AND BIOLOGICAL ACTIVITIES
OF CYCLIC ADP-CARBOCYCLIC-RIBOSE
AND ITS ANALOGS
Masayoshi Fukuoka, Satoshi Shuto,∗ Noriaki Minakawa,
Yoshihito Ueno, and Akira Matsuda
Graduate School of Pharmaceutical Sciences, Hokkaido University,
Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
ABSTRACT
An efficient synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic
for cyclic ADP-ribose, was achieved. Treatment of N1-carbocyclic-ribosyla-
denosine bisphosphate derivative 10 with AgNO3 in the presence of molecular
sieves 3A in pyridine gave the desired cyclic product in 93% yield, which was
deprotected to give the target cyclic ADP-carbocyclic-ribose (2).
Cyclic ADP-ribose (cADPR, 1)t is a newly discovered general mediator in-
volved in Ca2+ signaling (2). In cells, although cADPR is synthesized from NAD+
by ADP-ribosylcyclase and acts as a potent second messenger, it is hydrolyzed
promptly by cADPR hydrolase to give inactive ADP-ribose under physiological
conditions (2). cADPR is also known to be readily hydrolyzed non-enzymatically
at the unstable N-1 glycosidic linkage of its adenine moiety to give ADP-ribose,
even in neutral aqueous solution (3). Based on these findings, we designed cyclic
ADP-carbocyclic-ribose (2) and its inosine congener (3) (cyclic IDP-carbocyclic-
ribose), in which an oxygen atom in the ribose ring of cADPR is replaced by a
methylene group, as stable mimics of cADPR.
The synthesis of cADPR analogs has been extensively studied by enzy-
matic and chemo-enzymatic methods using ADP-ribosylcyclase from Aplysia
∗ Corresponding author.
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Copyright 2001 by Marcel Dekker, Inc.
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Californica, due to their biological importance (4). However the analogs that can be
obtained by this method are limited due to the substrate-specificity of the enzyme
(4). Accordingly, the development of flexible methods for synthesizing cADPR and
a variety of its analogs are needed.
We previously developed an efficient chemical method for the synthesis of
cyclic IDP-cabocyclic-ribose (3) using intramolecular condensation forming a py-
rophosphate linkage by the activation of the phenylthiophosphate group with I2 or
AgNO3 as the key step (5). In this paper, we report the efficient synthesis of cyclic
ADP-carbocyclic-ribose (2) using this method.
The synthesis of 2 is shown in Scheme 1. We planed to construct the N1-
carbocyclic-ribosyladenosine structure by modified Blackburn’s procedure (6). 4-
Methoxyimidate derivetive 5 was prepared by heating 5-cyano derivative 4 with
methyl orthoformate and the catalytic amount of CF3CO2H. The optically active
carbocyclic amine 6 was readily prepared from commercially available (1R)-
(-)-azabicyclo[2.2.1]hept-5-en-3-one (7). Treating a mixture of 5 and 6 with cat-
alytic amount of K2CO3 in MeOH gave N1-carbocyclic-ribosyladenosine deriva-
tive 7 in 83% yield. After the 5ꢁꢁ-hydroxyl of 7 was protected with a MMTr
group, it was treated with TBAF in THF to give 5ꢁꢁ-O-MMTr derivative 8. A
bis(phenylthio)phosphoryl group was introduced at the primary hydroxyl of the
ribose moiety with cyclohexylammonium S,S-diphenylphosphorodithioate(PSS)/
pyridine system (8), and then the 5ꢁꢁ-O-MMTr group was removed with aque-
ous AcOH to give 9. After the phosphorylation of 5ꢁꢁ-primary hydroxyl of 9 with
POCl3 in PO(OEt)3 at 0◦C, it was treated with H3PO2 in pyridine (8) to give
N1-carbocyclic-ribosyladenosine bisphosphate derivative 10. The intramolecular
condensation reaction was achived by treating 10 with AgNO3 and MS 3A in
pyridine to give the desired 11 in 93% yield. The two isopropylidene groups of

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1357
Scheme 1.
compound 11 was readily deprotected with formic acid, and target compound 2
was obtained in 88% yield.
ACKNOWLEDGMENT
This investigation was supported in part by a Grant from the Ministry of
Education, Science, Sports, and Culture of Japan.

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