18552-90-4Relevant 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.
Novel R-roscovitine NO-donor hybrid compounds as potential pro-resolution of inflammation agents
Montanaro, Gabriele,Bertinaria, Massimo,Rolando, Barbara,Fruttero, Roberta,Lucas, Christopher D.,Dorward, David A.,Rossi, Adriano G.,Megson, Ian L.,Gasco, Alberto
, p. 2107 - 2116 (2013/05/08)
Neutrophils play a pivotal role in the pathophysiology of multiple human inflammatory diseases. Novel pharmacological strategies which drive neutrophils to undergo programmed cell death (apoptosis) have been shown to facilitate the resolution of inflammation. Both the cyclin-dependent kinase inhibitor (CDKi) R-roscovitine and nitric oxide (NO) have been shown to enhance apoptosis of neutrophils and possess pro-resolution of inflammation properties. In order to search for new multi-target pro-resolution derivatives, here we describe the design, synthesis and investigation of the biological potential of a small series of hybrid compounds obtained by conjugating R-roscovitine with two different NO-donor moieties (compounds 2, 9a, 9c). The synthesized compounds were tested as potential pro-resolution agents, with their ability to promote human neutrophil apoptosis evaluated. Both compound 9a and 9c showed an increased pro-apoptotic activity when compared with either R-roscovitine or structurally related compounds devoid of the ability to release NO (des-NO analogues). Inhibition of either NO-synthase or soluble guanylate cyclase did not affect the induction of apoptosis by the R-roscovitine derivatives, similar to that reported for other classes of NO-donors. In contrast the NO scavenger PTIO prevented the enhanced apoptosis seen with compound 9a over R-roscovitine. These data show that novel compounds such as CDKi-NO-donor hybrids may have additive pro-resolution of inflammation effects.
Synthesis of purin-2-yl and purin-6-yl-aminoglucitols as C-nucleosidic ATP mimics and biological evaluation as FGFR3 inhibitors
Tak-Tak, Lotfi,Barbault, Florent,Maurel, Franois,Busca, Patricia,Le Merrer, Yves
experimental part, p. 1254 - 1262 (2011/04/23)
Two new series of C-nucleosidic ATP mimics have been synthesized using an efficient and versatile synthetic pathway. These compounds were designed as FGFR3 inhibitors using purine as a central scaffold. The two substituents, a polyhydroxylated ribose mimi
Synthesis of some biologically active halogenopurines
Hu, Yu Lin,Liu, Xiang,Lu, Ming,Ge, Qiang,Liu, Xiao Bin
experimental part, p. 429 - 436 (2010/12/29)
A series of some biologically active halogenopurines were synthesized from commercially available guanine (1). The reaction of guanine with acetic anhydride yielded 2,9-diacetylguanine (2-1) by acetylation reaction. Further treatment of 2-1 with POCl3 by PEG-2000 phase transfer catalysis furnished the important compound 3a, then 2-amino-6-halogenopurines (3b-d) were obtained through chlorine-exchange halogenations between KX and 3a by TPPB phase transfer catalyst. Further, 2-halogenopurines (2-2a-d, 4-2a-d, 5a-d) were efficiently prepared from 2-amino-6-substituted purines (1, 3a, 4-1) via a diazotization catalyzed by their corresponding CuX, and some new compounds 2-2a, 2-2c, 2-2d, 4-2c, 4-2d, 5b, 5c and 5d have been discovered. The structures of synthesized compounds were mainly established on the basis of their elemental analysis, 1H NMR, as well as their mass spectral data. All the title compounds were screened for their antifungal activities, and some of the compounds showed promising activity.
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.
Synthesis and full characterisation of 6-chloro-2-iodopurine, a template for the functionalisation of purines
Taddei, David,Kilian, Petr,Slawin, Alexandra M.Z.,Woollins, J. Derek
, p. 665 - 670 (2007/10/03)
A simple and efficient synthesis of 6-chloro-2-iodopurine from hypoxanthine has been achieved. This strategy relied on a regiospecific lithiation/quenching sequence of 6-chloro-9-(tetrahydropyran-2-yl)purine using Harpoon's base and tributyltin chloride. HMBC NMR studies on the product and intermediates confirmed the regioselectivity of this methodology. The molecular structures of the final dihalogenopurine and its 9-protected precursor were determined by single crystal X-ray diffraction.
2-Substitution of Adenine Nucleotide Analogues containing a Bicyclo[3.1.0]hexane Ring System Locked in a Northern Conformation: Enhanced Potency as P2Y1 Receptor Antagonists
Kim, Hak Sung,Ohno, Michihiro,Xu, Bin,Kim, Hea Ok,Choi, Yongseok,Ji, Xiao D.,Maddileti, Savitri,Marquez, Victor E.,Harden, T. Kendall,Jacobson, Kenneth A.
, p. 4974 - 4987 (2007/10/03)
Preference for the northern (N) ring conformation of the ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of P2Y 1 receptors was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose su
ALKYNYLPURINE COMPOUNDS AND PRODUCTION METHODS THEREOF
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Page 43, 44, (2008/06/13)
The present invention relates to alkynylpurine compounds represented by the following formula (I-1) and the formula (I-2): wherein each symbol is as defined in the present specification, salts thereof, and production methods thereof. According to the pres
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.
