PDF(Pubmed)
Abstract：
New amide conjugates of hydroxycinnamic acids (HCAs) and the known antineoplastic 5,11-dimethyl-5H-indolo[2,3-b]quinoline (DiMIQ), an analog of the natural alkaloid neocryptolepine, were synthesized and tested in vitro for anticancer activity. The compound 9-[((2-hydroxy)cinnamoyl)amino]-5,11-dimethyl-5H-indolo[2,3-b]quinoline (2), which contains the ortho-coumaric acid fragment, demonstrated dose-dependent effectiveness against both normal BxPC-3 and metastatic AsPC-1 pancreatic cancer cells. The IC50 values for AsPC-1 and BxPC-3 were 336.5 nM and 347.5 nM, respectively, with a selectivity index of approximately 5 for both pancreatic cancer cells compared to normal dermal fibroblasts. Conjugate 2 did not exhibit any hemolytic activity against human erythrocytes at the tested concentration. Computational studies were performed to predict the pharmacokinetic profile and potential mechanism of action of the synthesized conjugates. These studies focused on the ADME properties of the conjugates and their interactions with DNA, as well as DNA-topoisomerase alpha and beta complexes. All of the conjugates studied showed approximately one order of magnitude stronger binding to DNA compared to the reference DiMIQ, and approximately two orders of magnitude stronger binding to the topoisomerase II-DNA complex compared to DiMIQ. Conjugate 2 was predicted to have the strongest binding to the enzyme-DNA complex, with a Ki value of 2.8 nM.
摘要：
羟基肉桂酸（HCA）和已知的抗肿瘤5,11-二甲基-5H-吲哚并[2,3-b]喹啉（DiMIQ）的新酰胺共轭物，天然生物碱的类似物，合成并在体外测试抗癌活性。化合物9-[((2-羟基)肉桂酰基)氨基]-5,11-二甲基-5H-吲哚并[2,3-b]喹啉(2),其中含有邻香豆酸片段，证明了对正常BxPC-3和转移性AsPC-1胰腺癌细胞的剂量依赖性有效性。AsPC-1和BxPC-3的IC50值分别为336.5nM和347.5nM，分别,与正常真皮成纤维细胞相比，两种胰腺癌细胞的选择性指数约为5。缀合物2在测试浓度下不表现出对人类红细胞的任何溶血活性。进行计算研究以预测合成缀合物的药代动力学特征和潜在作用机制。这些研究集中在缀合物的ADME性质及其与DNA的相互作用，以及DNA拓扑异构酶α和β复合物。与参考DiMIQ相比，所有研究的缀合物显示与DNA的结合强度约为一个数量级，与DiMIQ相比，与拓扑异构酶II-DNA复合物的结合强度约为两个数量级。预计缀合物2与酶-DNA复合物的结合最强，Ki值为2.8nM。
