Zhao Xin, Gu Jun, Yin Dali, Chen Xiaoguang
Department of Pharmacology, Institute of Materia Medica, Chinese Academic of Medical Science and Peking Union Medical College, 1 Xian Nong Tan Street, Beijng 100050, China.
Bioorg Med Chem Lett. 2004 Sep 20;14(18):4767-70. doi: 10.1016/j.bmcl.2004.06.089.
Three novel taxinine analogues were prepared and tested for their activity as multidrug resistance (MDR) reversal agents in comparison with verapamil. In vitro testing demonstrated that compounds 8-10 possess MDR-reversal activity in the KB/V cell line. Half-hour after treatment with 5, 10, and 20 micromol/L compound 9, the intracellular rhodamine123 concentration increased 2.3, 2.9, and 3.2-fold, respectively, higher than 1.88-fold of 10 micromol/L verapamil in KB/V cell line. In vivo studies with VCR-resistant KB/V tumor xenografts showed that compound 9 in combination with VCR significantly inhibited tumor growth. Treatment with VCR or 9 alone did not result in growth inhibition. These results reveal that three taxinine analogues are good modifiers of MDR in tumor cells.
制备了三种新型紫杉宁类似物，并与维拉帕米比较，测试了它们作为多药耐药（MDR）逆转剂的活性。体外测试表明，化合物8 - 10在KB/V细胞系中具有MDR逆转活性。用5、10和20 μmol/L化合物9处理半小时后，KB/V细胞系中细胞内罗丹明123浓度分别增加了2.3倍、2.9倍和3.2倍，高于10 μmol/L维拉帕米的1.88倍。对长春新碱耐药的KB/V肿瘤异种移植的体内研究表明，化合物9与长春新碱联合使用可显著抑制肿瘤生长。单独使用长春新碱或化合物9均未导致生长抑制。这些结果表明，三种紫杉宁类似物是肿瘤细胞中MDR的良好调节剂。
