應用延長駐留時間概念於喹啉衍生物作為潛能雙靶點Bcr-Abl/C-Src 蛋白質激酶抑制劑之開發

Abstract

Abstract To reduce the side effect induced by off-target effect, the concept of the residence time was utilized to design and synthesize three series of quinoline derivative based on lead compound, 4-((2,4-dichloro-5-methoxyphenyl)-amino)-6- methoxy-7-(3-(4 -methyl-1-piperazinyl)-propoxy)-3-quinoline-carbonitrile (2), as potential Bcr-Abl/ c-Src dual inhibitors. An acryloyl functional group was introduced onto the C4 position of quinoline and expected to form the reversible covalent bond to prolong the residence time. After introducing an acryloly functional group onto quinoline, it was found very difficult to identify the structure by NMR. It is considered because of the steric hindrance which made the compound exist in many conformational isomers. Therefore, the compound after a series of studied and the notion finally confirmed. In this investigation, found that the compounds with long chain at C6 or C7 showed better enzymatic inhibitory activity. It was also noted that quinoline (45a, 45b, 46a 46b) with the long chain at C6 showed the good selectivity between Bcr-Abl and C-Src. However, those compounds having the long chain at C7 of quinoline demonstrated good enzymatic inhibitory activity against both the Bcr-Abl and C-Src. Although the compounds with acryloyl group showed 1000-fold weaker activity than those of compounds without acryloyl group, the result of cytotoxicity assay revealed that anti-proliferation activity was in the same category. Furthermore, 37 with acetyl group instead of acryloly was synthesized and did not show any significantly activity against different cancer cell lines, indicating that the acryloyl group played a key role of binding interaction with target enzymes to enhance the inhibitory activity.