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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 nM and 78 nM.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.“,”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 IC50 =0.6 μM (8-fold of EMB-3) on BT474 breast tumor cells.Compound 6d inhibited epidermal growth factor receptor (EGFR,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 t1/2 of 1.7 h.These results indicated that compound 6d was a potential lead compound for the treatment of breast cancer.