915019-51-1Relevant articles and documents
Development of a Robust Synthesis of Dactolisib on a Commercial Manufacturing Scale
Baenziger, Markus,Pachinger, Werner,Stauffer, Frédéric,Zaugg, Werner
, p. 1908 - 1917 (2019/09/30)
The development of the robust synthesis of 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]-phenyl]propionitrile (dactolisib) on a commercial scale is described. The key step is a Pd-catalyzed Suzuki coupling of 2-[4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)-phenyl]-2-methyl-propionitrile to 3-quinoline boronic acid. A special focus is placed on reducing the amount of Pd catalyst used in the Suzuki coupling and purifying the crude drug substance, including removing traces of Pd.
Design, synthesis, and antitumor evaluation of quinoline-imidazole derivatives
Xiao, Zhen,Lei, Fei,Chen, Xiuying,Wang, Xiaolei,Cao, Lujie,Ye, Kejun,Zhu, Wufu,Xu, Shan
, (2018/05/14)
A series of compounds bearing quinoline-imidazole (8a–e, 9a–e, 10a–e, 11a–e, and 12a–e) not reported previously were designed and synthesized. The target compounds were evaluated for antitumor activity against A549, PC-3, HepG2, and MCF-7 cells by the MTT method, with NVP-BEZ235 being the positive control. Most compounds showed moderate activity and compound 12a showed the best activity against HepG2, A549, and PC-3 cells, with half-maximal inhibitory concentration (IC50) values of 2.42 ± 1.02 μM, 6.29 ± 0.99 μM, and 5.11 ± 1.00 μM, respectively, which was equal to NVP-BEZ235 (0.54 ± 0.13 μM, 0.36 ± 0.06 μM, 0.20 ± 0.01 μM). Besides, the IC50 value of 12a against the cell line WI-38 (human fetal lung fibroblasts) was 32.8 ± 1.23 μM, indicating that the target compounds were selective for cancer cells. So, 11a and 12a were evaluated against PI3Kα and mTOR to find out if the compounds acted through the PI3K-Akt-mTOR signal transduction pathway. The inhibition ratios to PI3Kα and mTOR were slightly lower than that of NVP-BEZ235, suggesting there may be some other mechanisms of action. The structure–activity relationships and docking study of 11a and 12a revealed that the latter was superior. Moreover, the target compounds showed better in vitro anticancer activity when the C-6 of the quinoline ring was replaced by a bromine atom.
Novel quinoline-derived mTOR inhibitors with remarkable enzymatic and cellular activities: Design, synthesis and biological evaluation
Ma, Xiao-Dong,Qiu, Ni,Yang, Bo,He, Qiao-Jun,Hu, Yong-Zhou
, p. 297 - 310 (2016/03/01)
Herein, we reported the preparation and in vitro development of a novel series of quinoline-based mTOR inhibitors, some of which were obtained via introducing a ring-opening strategy. As for enzymatic activity, more than half of these quinoline derivatives exhibited moderate to potent inhibition against mTOR. Among them, six compounds showed IC50 values below 50 nM. In particular, several quinolines exhibited remarkably enhanced anti-proliferative activities against all the three tested tumor cell lines in contrast to the initial lead 9. As a representative in this series, compound 24 demonstrated IC50 values of 0.11, 0.17 and 0.04 μM against HCT-116, PC-3 and MCF-7 cell lines, respectively. Besides, compounds 17 and 24 were identified to be selective over class I PI3Ks. Further Western blot analysis validated the dual inhibition of mTORC1 and mTORC2 as a result of compound 24 treatment in the MCF-7 cell line, which was beneficial for conquering the S6K/IRS1/PI3K negative feedback loop. Moreover, acceptable stability was displayed by compound 17, another representative of this series, in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), as well as rat liver microsome (RLM). By virtue of the favorable biological profiles, several quinolines merit further in vivo investigation.
