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Nucleosides and Nucleotides. 173. Synthesis of Cyclic IDP-carbocyclic-ribose, a Stable Mimic of Cyclic ADP-ribose. Significant Facilitation of the Intramolecular Condensation Reaction of N-1-(Carbocyclic-ribosyl)inosine 5‘,6‘‘-Diphosphate Derivatives by an 8-Bromo-Substitution at the Hypoxanthine Moiety
journal contribution
posted on 1998-02-27, 00:00 authored by Satoshi Shuto, Michiyo Shirato, Yuji Sumita, Yoshihito Ueno, Akira MatsudaCyclic ADP-ribose (cADPR, 1) is a general mediator
involved in cellular Ca2+ signaling.
However,
both the biological and chemical instability of cADPR limit studies on
its physiological role. We
designed cyclic ADP-carbocyclic-ribose (3) and its inosine
congener 4 as stable mimics of cADPR
and successfully synthesized 4. Starting with
cyclopentadiene, the optically active carbocyclic unit
8 was constructed via enzymatic optical resolution.
SN2 reactions of 8 with inosine derivative
7
and the 8-bromoinosine derivative 25 gave the
N-1-substituted derivatives 6 and 26,
which were
converted to the corresponding diphosphate derivatives 5 and
22. The intramolecular condensation
reactions between the two phosphate groups of 5 and
22 were investigated. Although the
reaction
with inosine derivative 5 did not produce any of the
cyclization product 20, treatment of the
corresponding 8-bromoinosine derivative 22 with EDC gave the
desired intramolecular condensation
product 29 in 23% yield. Thus, the significant effect
of the 8-bromo group at the hypoxanthine
moiety in facilitating the key intramolecular condensation reaction
between the phosphate groups
of the substrate 22 was recognized. This is possibly
due to conformational restriction of the molecule
in a syn-form around its glycosyl linkage. The 8-bromo and
isopropylidene groups were removed
in succession to give the target compound 4. This is
the first total synthesis of this type of cyclic
nucleotide.
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intramolecular condensation reactionsdiphosphate derivatives 5S N 2 reactionscADPR limit studiestarget compound 4intramolecular condensation reactioncarbocyclic unit 8inosine congener 4EDCbromoinosinecyclization product 20Intramolecular Condensation Reactionintramolecular condensation product 29Cyclicbromophosphate groups
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