A new synthetic route to (North)-methanocarba nucleosides designed as A3 adenosine receptor agonists.
Activation of the A3 adenosine receptor (AR) is associated with cerebroprotective, cardioprotective, and anticancer effects. Among potent and selective A3 AR agonists are novel methanocarba adenosine analogues in which the conformation of a pseudo-ribose moiety is locked in the North (N) hemisphere of the pseudorotational cycle. 5'-Uronamide (N)-methanocarba nucleosides, such as MRS1898 and MRS2346, are examples of full agonists of the human A3 AR. An improved convergent approach from easily accessible 2,3-O-isopropylidene-d-erythrose (2b), and the combination of a strategic intramolecular cyclopropanation step plus the acid-catalyzed isomerization of an isopropylidene group, provided a suitable pseudosugar precursor (23) for the synthesis of MRS1898, MRS2346, and related analogues. This new synthetic route uses readily available building blocks and opens the way for the preparation of a variety of targets on a reasonable scale.
Joshi
Bhalchandra V
BV
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS Bethesda, Maryland 20892, USA.
Moon
Hyung Ryong
HR
Fettinger
James C
JC
Marquez
Victor E
VE
Jacobson
Kenneth A
KA
D058909:Adenosine A3 Receptor Agonists; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D058909:Adenosine A3 Receptor Agonists; D003517:Cyclopentanes; D009705:Nucleosides