Design,synthesis and anti-tumor activities of cyclic phosphoramidate mustard-quinazoline conjugates  

环状磷酰胺氮芥-喹唑啉偶联物的设计、合成及抗肿瘤活性（英文）

作　　者：陈加贝 郑育奋 孔维崎 李鑫 罗来春 韩彦君 林松文 孙崎 葛泽梅 李润涛 

机构地区：[1]北京大学医学部药学院化学生物学系 [2]天然药物及仿生药物国家重点实验室,北京100191

出　　处：《Journal of Chinese Pharmaceutical Sciences》2017年第10期727-736,共10页中国药学（英文版）

基　　金：Ministry of Science and Technology of China(Grant No.2012ZX09103101-042)

摘　　要：A series of new cyclic phosphoramidate mustard-quinazoline conjugates were designed and synthesized based on the drug candidate EMB-3, a multi-target-directed ligand against tumor cells, and their anti-tumor activities were evaluated on breast cancer and lung cancer cells. Compound 6d exhibited the best anti-tumor performance with IC5o = 0.6 pM （8-fold of EMB-3） on BT474 breast tumor cells. Compound 6d inhibited epidermal growth factor receptor （EGFIL biomarker for NSCLC） and human epidermal growth factor 2 （HER2, biomarker for breast cancer） with IC50 of 18 nM and 78 nM, respectively. The preliminary pharmacokinetic study revealed that 6d was more stable than EMB-3 during the in vivo metabolism. A single dose per os （PO） administration of 6d in rat model （10 mg/kg） resulted in a moderate tl/2 of 1.7 h. These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.依据多靶点候选药物EMB-3,作者设计了一系列环状磷酰胺氮芥-喹唑啉偶联物并对其肺癌和乳腺癌细胞株的抑制作用进行了评价。其中化合物6d活性最强,对BT474乳腺癌细胞株的抑制活性达到了IC50=0.6μM,是EMB-3活性的8倍。以化合物6d为分子探针对其作用靶点进行确认,结果显示其对表皮生长因子受体-1和表皮生长因子受体-2的酶抑制活性分别为18 n M and 78 n M。初步体内药物代谢实验发现单剂量口服给药化合物6d(10 mg/kg),大鼠的体内代谢半衰期为1.7小时,比先导物EMB-3稳定。以上研究结果表明:化合物6d是一个对乳腺癌肿瘤株BT474具有明显抑制活性的化合物,值得进一步研究。

关 键 词：Phosphoramidate mustard conjugate ANTI-TUMOR Breast cancer EGFR/HER2 

分 类 号：R914[医药卫生—药物化学] R96[医药卫生—药学]