Synthesis of novel diterpenoid analogs with in-vivo antitumor activity
Synthesis of novel diterpenoid analogs with in-vivo antitumor activity
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具有体内抗肿瘤活性的新型二萜类似物的合成
DOI：
10.1016/j.ejmech.2016.04.071
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发表时间：
2016-09-14
影响因子：
6.7
通讯作者：
Qiu, Wen-Wei
中科院分区：
文献类型：
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作者：
Wang, Ying-Ying;He, Yuan;Qiu, Wen-Wei
先导化合物7具有抗肿瘤作用，这是通过筛选我们的小合成天然产物样化合物（NPL）库发现的。基于先导化合物，合成了一系列新的三环二萜类似物，并使用磺酰罗丹明B（SR B）测定法研究了它们对各种肿瘤细胞系生长的活性。令人高兴的是，大多数芳香酰胺化合物显示出比先导化合物更强的抗肿瘤活性。最具活性的化合物19（QW30）显示平均IC 50为0.33 μ M，其效力是先导化合物的15倍。与肿瘤细胞系相比，大多数具有有效抗肿瘤活性的化合物对正常人成纤维细胞（HAF）的毒性较小。尤其是19，其对HAF和癌细胞系的选择性指数（SI）是阳性对照化合物鬼臼毒素的17.3倍。用T47D细胞系进行7和19的凋亡、集落形成和transwell迁移实验。在T47D荷瘤小鼠体内也观察到19的体内抗肿瘤作用，未见明显毒性。(C)2016 Elsevier Masson SAS。All rights reserved.
A lead compound 7 has antitumor effect, which was discovered by screening our small synthetic natural product-like compound (NPL) library. Based on the lead compound, a series of novel tricyclic diterpene analogs were synthesized and investigated for their activity against the growth of various tumor cell lines using the sulforhodamine B (SRB) assay. To our delight, most aromatic amide compounds exhibited more potent antitumor activity than the lead compound. The most active compound 19 (QW30) showed an average IC50 0.33 mu M, which was 15-fold more potent than the lead compound. Most of the compounds with potent antitumor activity displayed less toxic on normal human fibroblasts (HAF) in comparison with the tumor cell lines. Especially 19, its selectivity indexes (SI) between HAF and cancer cell lines was 17.3 times better than the positive control compound podophyllotoxin. The apoptosis, colony formation and transwell migration assays of 7 and 19 were performed on T47D cell line. The in-vivo antitumor effect of 19 was also observed in T47D tumor-bearing mice without obvious toxicity. (C) 2016 Elsevier Masson SAS. All rights reserved.