- Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: Structure-based virtual screening, optimization and biological evaluation
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Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5′-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.
- Qiu, Xiaoxia,Huang, Yiyou,Wu, Deyan,Mao, Fei,Zhu, Jin,Yan, Wenzhong,Luo, Hai-Bin,Li, Jian
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p. 119 - 133
(2017/11/30)
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- Synthetic method of 2-(3,3,3-trifluoropropylthio) adenosine
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The invention belongs to the field of medicinal chemistry synthesis and discloses a synthetic method of 2-(3,3,3-trifluoropropylthio) adenosine. The method comprises the following steps: firstly performing nucleophilic substitution between 2-Chloroadenine (as shown in a formula I) as a raw material and tetraacetylribofuranose in a first solvent under a function of catalyst SnCl4 to obtain a compound (as shown in a formula II); performing hydrolysis reaction on the compound (as shown in the formula II) in a second solvent under a function of alkali a to obtain a compound (as shown in formula a III); finally performing nucleophilic substitution on the compound (as shown in the formula III) and 3,3,3-trifluoro-propanethiol under a function of alkali b to obtain a compound (as shown in a formula IV), namely 2-(3,3,3-trifluoropropylthio) adenosine. The synthetic method in the invention is simple in lines, high in yield and low in cost, and raw materials are low in cost and easy to obtain.
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Paragraph 0007; 0035-0069
(2017/08/30)
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- Pd-catalysed amidation of 2,6-dihalopurine nucleosides. Replacement of iodine at 0 °c
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Pd-catalysed reactions of 2-Cl, 2-Br and 2-I derivatives of a 6-chloropurine nucleoside with benzamide have been compared, using Pd 2dba3, Xantphos and Cs2CO3 in toluene, between 20 and 80 °C. The reactivity order was 2-I > 2-Br > 6-Cl ? 2-Cl. The 2-I substituent could be replaced even at 0 °C, under conditions disclosed here for the first time. On the other hand, the replacement of the chlorine atom at position 2 (2-Cl) required 110 °C.
- Bosch, Lluís,Cial?cu, Ionela,Caner, Joaquim,Ariza, Xavier,Costa, Anna M.,Terrazas, Montserrat,Vilarrasa, Jaume
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body text
p. 1358 - 1362
(2012/04/10)
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- A new synthesis of 2-chloro-2'-deoxyadenosine (Cladribine), CdA)
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A new efficient route for the synthesis of 2-chloro-2';-deoxyadenosine (Cladribine), CdA) has been developed. The key step of this method was selective deprotection of the acetyl group at the 2' position; the 3', 5' acetyl groups were not affected. This can be accomplished efficiently with hydroxylamine hydrochloride and sodium acetate in pyridine. The 2' hydroxyl group was removed by the Barton-McCombie reaction. Using this strategy, CdA was prepared in five steps and 31.0% yields. Copyright Taylor and Francis Group, LLC.
- Xu, Shaohong,Yao, Peng,Chen, Gairong,Wang, Hui
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experimental part
p. 353 - 359
(2011/11/12)
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