Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl
Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl
复制标题
新型水溶性雷公藤甲素衍生物的设计、合成和生物学评价：对携带 T315I 突变体 Bcr-Abl 的伊马替尼耐药 CML 细胞的抗肿瘤活性
DOI：
10.1016/j.bmc.2010.01.052
复制
发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Pan, Jingxuan
中科院分区：
文献类型：
--
作者：
Xu, Fang;Shi, Xianping;Pan, Jingxuan
伊马替尼（STI 571）是治疗慢性粒细胞白血病（CML）的一线靶向治疗药物。然而，由于Bcr-Abl激酶结构域的点突变而对伊马替尼产生耐药性是一个新出现的问题。我们最近报道雷公藤内酯醇本研究设计了一系列C-14位羟基被不同胺酯取代的雷公藤内酯醇衍生物（3-18）：3-6和13 7-9、11、12和15-18（不同尺寸的脂环族胺酯）和10和14（芳烷基胺酯）。在增殖抑制、凋亡和信号转导方面检测了化合物对CML细胞（包括KBM 5-T315 I细胞）的抑制活性。裸鼠异种移植模型也用于评价体内活性。化合物2-9、11-14、17和18对KBM 5和KBM 5-T315 I细胞表现出有效的抑制活性。该系列衍生物下调Bcr-Abl mRNA表达。用免疫印迹进一步检查化合物4、5、8和9对信号传导和细胞凋亡的影响。选择化合物5用于在裸鼠异种移植模型中评估。C-14基团的立体位阻可能是其抗肿瘤作用的主要原因。计算小分子-蛋白质对接分析说明了化合物9和RNA聚合酶II之间可能的相互作用。我们的研究结果表明，这一系列的衍生物可能是有前途的代理，以克服伊马替尼耐药所造成的Bcr-Abl-T315 I突变。(C)2010爱思唯尔有限公司保留所有权利。
Imatinib (STI571) is the frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML). However, resistance to imatinib due to point mutations in Bcr-Abl kinase domain is an emerging problem. We recently reported that triptolide (compound 1) could effectively kill CML cells including those harboring T315I mutant Bcr-Abl. In the present study, we designed a series of C-14 triptolide derivatives with C-14-hydroxyl substituted by different amine esters (3-18): 3-6 and 13 (by aliphatic chain amine esters); 7-9, 11, 12 and 15-18 (by alicyclic amine esters with different size), and 10 and 14 (by aralkylamine esters). The compounds were examined for their antineoplastic activity against CML cells (including KBM5-T315I cells) in terms of proliferation inhibition, apoptosis and signal transduction. Nude mouse xenograft model was also used to evaluate the in vivo activity. Compounds 2-9, 11-14, 17 and 18 exhibited a potent inhibitory activity against KBM5 and KBM5-T315I cells. This series of derivatives down-regulated Bcr-Abl mRNA. Compounds 4, 5, 8 and 9 were further examined for their impact on signaling and apoptosis with immunoblotting. Compound 5 was chosen for evaluation in a nude mouse xenograft model. The stereo-hindrance of C-14 group appeared to be responsible for the antitumor effect. The computational small molecule-protein docking analysis illustrated the possible interaction between compound 9 and RNA polymerase II. Our results suggest that this series of derivatives may be promising agents to overcome imatinib-resistance caused by the Bcr-Abl-T315I mutation. (C) 2010 Elsevier Ltd. All rights reserved.