403620-89-3Relevant articles and documents
Discovery and Structure-Activity Relationships of Novel Template, Truncated 1′-Homologated Adenosine Derivatives as Pure Dual PPARγ/δModulators
An, Seungchan,Kim, Gyudong,Kim, Hyun Jin,Ahn, Sungjin,Kim, Hyun Young,Ko, Hyejin,Hyun, Young Eum,Nguyen, Mai,Jeong, Juri,Liu, Zijing,Han, Jinhe,Choi, Hongseok,Yu, Jinha,Kim, Ji Won,Lee, Hyuk Woo,Jacobson, Kenneth A.,Cho, Won Jea,Kim, Young-Mi,Kang, Keon Wook,Noh, Minsoo,Jeong, Lak Shin
, p. 16012 - 16027 (2021/01/09)
Following our report that A3 adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1′-homologated adenosine analogues 4a-4t, as dual PPARγ/δmodulators without AR binding. Removal of binding affinity to A3AR was achieved by 1′-homologation, and PPARγ/δdual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPARγ/δbut lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγaffinity, indicating that the C2 position defines a pharmacophore for selective PPARγligand designs. PPARγ/δdual modulators functioning as both PPARγpartial agonists and PPARδantagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.
Linear and convergent approaches to 2-substituted adenosine-5′-N-alkylcarboxamides
Foitzik, Richard C.,Devine, Shane M.,Hausler, Nicholas E.,Scammells, Peter J.
experimental part, p. 8851 - 8857 (2009/12/26)
Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield). Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in 15% yield from guanosine over nine steps. 2-Iodoadenosine-5′-N-ethylcarboxamide (13) was subsequently converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation of?potent A2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of 2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-5′-N-ethylcarboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of adenosine analogues with varied 2-, 6- and 5′-substitution patterns.
Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin bound 6-thiopurines
Brun, Virginie,Legraverend, Michel,Grierson, David S
, p. 7911 - 7923 (2007/10/03)
The preparation of 6-chloro-2-iodo-9-tetrahydropyranylpurine (2), was achieved in three high yield steps from 6-chloropurine. This derivative was then selectively substituted at C-6 by reaction with a benzylthiol to give 3, a versatile intermediate for the synthesis of 2,6,9-trisubstituted purines. Reaction of 3 in palladium-catalyzed cross-coupling reactions, (including Sonogashira coupling at room temperature), as well as nucleophilic substitutions with amines occurred selectively at C-2. The 6-thiobenzyl substituent was activated through oxidation to the corresponding sulfone and replaced by various benzyl or phenyl amines. This strategy was subsequently adapted to solid support, wherein 23 is connected to Merrifield resin via a 6-thiovaleric ester linker. The presence of the linker, in combination with the use of palladacycle type catalysts improved the yield of palladium(0)-catalyzed Suzuki and Sonogashira cross-coupling reactions. This strategy opens a new route to combinatorial chemistry library synthesis of trisubstituted purines on the solid support.
