Wang Lei, Xie Shao, Ma Longjun, Chen Yi, Lu Wei
School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
Bioorg Med Chem. 2015 May 1;23(9):1950-62. doi: 10.1016/j.bmc.2015.03.031. Epub 2015 Mar 18.
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 compound 36o (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 of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.
设计并合成了15种具有α-甲氧基取代E环的新型喜树碱衍生物。与SN-38相比，所有衍生物均表现出相似或更高的细胞毒性，并且它们在无细胞试验中以与SN-38相似的方式抑制拓扑异构酶I活性，证实它们代表了一类新的拓扑异构酶I抑制剂。值得注意的是，水溶性化合物36o（1.2mg/mL）表现出更高的内酯稳定性，在0.5mg/kg和3.0mg/kg剂量下，在使用人结肠癌细胞系HT-29的异种移植模型小鼠中显示出显著的抗肿瘤活性。基于这些阳性结果，进一步开发与36o相关的化合物作为潜在的抗癌临床试验候选药物是完全有必要的。
