Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents.
Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents.
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DOI：
10.1016/j.bmc.2015.03.031
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发表时间：
2015-05
影响因子：
3.5
通讯作者：
Lei Wang;S. Xie;Longjun Ma;Yi Chen;Wei Lu
中科院分区：
文献类型：
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作者：
Lei Wang;S. Xie;Longjun Ma;Yi Chen;Wei Lu
设计并合成了15个带有α-OMe取代E环的高喜树碱类化合物。所有的衍生物都表现出与SN-38相似或更强的细胞毒性，并且它们在无细胞实验中以与SN-38相似的方式抑制Topo I的活性，证实它们代表了一类新的Topo I抑制剂。值得注意的是，水溶性化合物36O(1.2 mg/mL)表现出增强的内酯稳定性，在0.5 mg/kg和3.0 mg/kg时，它在携带人结肠癌细胞株HT-29的异种移植模型的小鼠中显示出显著的抗肿瘤活性。在这些积极结果的基础上，进一步开发与360相关的化合物作为潜在的抗癌临床试验候选者是肯定的。
Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound36o(1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.