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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 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。
Based on the multi-target candidate EMB-3, the authors designed a series of cyclic phosphoramide mustard-quinazoline conjugates and evaluated their inhibitory effects on lung and breast cancer cell lines. Among them, compound 6d had the strongest activity and reached IC50 = 0.6μM for BT474 breast cancer cell line, which was 8 times of that of EMB-3. Compound 6d was used as a molecular probe to confirm its target of action. The results showed that the inhibitory activity of 6d on EGFR-1 and EGFR-2 was 18 nM and 78 nM, respectively. A preliminary in vivo pharmacokinetic study found that a single oral dose of compound 6d (10 mg / kg) resulted in a 1.7-h metabolism half-life in rats, more stable than the lead EMB-3. The above results show that: Compound 6d is a compound that has obvious inhibitory activity on breast cancer BT474, which is worth further study.