In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid Malignancies
In Vitro and in Vivo Evaluation of Fully Substituted (5-(3-Ethoxy-3-oxopropynyl)-4-(ethoxycarbonyl)-1,2,3-triazolyl-glycosides as Original Nucleoside Analogues to Circumvent Resistance in Myeloid Malignancies
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DOI：
10.1021/acs.jmedchem.6b01803
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发表时间：
2017-02-23
影响因子：
7.3
通讯作者：
Benhida, Rachid
中科院分区：
文献类型：
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作者：
Amdouni, Hella;Robert, Guillaume;Benhida, Rachid
采用直接点击/亲电加成或点击/氧化偶联的方法合成了一系列含1，4，5-三取代-1，2，3-三氮唑苷酮的核苷类似物。通过细胞培养分析，发现了一系列属于5-炔基-1，2，3-三氮唑家族的化合物，这些化合物对包括慢性粒细胞白血病(CML)和骨髓增生异常综合征(MDS)在内的几种血液系统恶性肿瘤显示出强大的抗白血病作用，这些疾病对各自的治疗敏感或耐药。化合物4a在小鼠体内对SKM1-R MDS细胞株的移植也是有效的。此外，对其作用模式的一些研究表明，该化合物通过caspase和自噬诱导细胞死亡。
yy A series of nucleoside analogues bearing a 1,4,5-trisubstituted-1,2,3-triazole aglycone was synthesized using a straightforward click/electrophilic addition or click/oxidative coupling tandem procedures. SAR analysis, using cell culture assays, led to the discovery of a series of compounds belonging to the 5-alkynyl-1,2,3-triazole family that exhibits potent antileukemic effects on several hematologic malignancies including chronic myeloid leukemia (CML) and myelodysplastic syndromes (MDS) either sensitive or resistant to their respective therapy. Compound 4a also proved efficient in-vivo on mice xenografted with SKM1-R MDS cell line. Additionally, some insights in its mode of action revealed that this compound induced cell death by caspase and autophagy induction.