Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.
Synthesis, activity, and pharmacophore development for isatin-beta-thiosemicarbazones with selective activity toward multidrug-resistant cells.
复制标题
DOI：
10.1021/jm800861c
复制
发表时间：
2009-05-28
影响因子：
7.3
通讯作者：
Gottesman MM
中科院分区：
文献类型：
--
作者：
Hall MD;Salam NK;Hellawell JL;Fales HM;Kensler CB;Ludwig JA;Szakács G;Hibbs DE;Gottesman MM
我们最近已经确定了一类新的化合物，选择性地杀死细胞表达P-糖蛋白（P-gp，MDR 1），ATP酶外排泵，赋予癌细胞的多药耐药性。我们初步研究的几种靛红-β-缩氨基硫脲已得到验证，并合成和测试了一系列类似物。许多研究表明，MDR 1选择性活性优于先导化合物NSC 73306（1）。产生用于细胞毒性和MDR 1选择性的药效团以描绘活性所需的结构特征。MDR 1选择性药效团突出了缩氨基硫脲N4位芳香/疏水特征的重要性，以及对靛红部分作为关键生物电子等排贡献者的依赖。此外，一个定量构效关系（QSAR）模型，产生了交叉验证的相关系数为0.85，有效地预测未经测试的缩氨基硫脲的细胞毒性。总之，模型作为有效的方法来预测结构与MDR 1选择性活性，并帮助指导1的作用机制的搜索。
We have recently identified a new class of compounds that selectively kill cells that express P-glycoprotein (P-gp, MDR1), the ATPase efflux pump that confers multidrug resistance on cancer cells. Several isatin-β-thiosemicarbazones from our initial study have been validated, and a range of analogs synthesized and tested. A number demonstrated improved MDR1-selective activity over the lead, NSC73306 (1). Pharmacophores for cytotoxicity and MDR1-selectivity were generated to delineate the structural features required for activity. The MDR1-selective pharmacophore highlights the importance of aromatic/hydrophobic features at the N4 position of the thiosemicarbazone, and the reliance on the isatin moiety as key bioisosteric contributors. Additionally, a quantitative structure-activity relationship (QSAR) model that yielded a cross-validated correlation coefficient of 0.85 effectively predicts the cytotoxicty of untested thiosemicarbazones. Together, the models serve as effective approaches for predicting structures with MDR1-selective activity, and aid in directing the search for the mechanism of action of 1.
登录
查看更多内容
影响因子：
15
作者：
CARPINO, LA
通讯作者：
CARPINO, LA
DOI：
10.1073/pnas.70.1.164
发表时间：
1973-01-01
影响因子：
11.1
作者：
LEVINSON, W;FARAS, A;BISHOP, JM
通讯作者：
BISHOP, JM
影响因子：
3.5
作者：
Dixon, Steven L.;Smondyrev, Alexander M.;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
3.3
作者：
DEAN, RT;NICHOLSON, P
通讯作者：
NICHOLSON, P
影响因子：
6.7
作者：
Karali, N
通讯作者：
Karali, N