Synthesis and Biological Evaluation of 4‐Phenoxy‐6,7‐disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c‐Met Inhibitors

Abstract

Novel quinoline derivatives bearing acyclic semicarbazones were prepared and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for their c-Met kinase inhibitory activity and their cytotoxicity against the cell lines HT-29, MKN-45, and MDA-MB-231 in vitro. Several potent compounds were further evaluated against A549 cells. Most compounds displayed moderate to excellent activity, and the structure-activity relationship studies identified the most promising compound 35 as a selective c-Met kinase inhibitor (IC50 = 4.3 nM). Compound 35 showed a 3.5- and 18.8-fold increase in cytotoxicity in vitro against HT-29 and A549 cells, respectively, compared to that of foretinib. Poor off-target effects of compound 35 were further confirmed by the antiproliferative activity against the c-Met inhibition less sensitive MDA-MB-231 cell line (IC50 = 0.77 µM).

Design and Synthesis of Novel 4‐Phenoxyquinolines Bearing 3‐Hydrosulfonylacrylamido or 1H‐Imidazole‐4‐carboxamido Scaffolds as c‐Met Kinase Inhibitors

“…Scheme depicts the preparation of compounds 20–29 . The key intermediates of 4‐(2‐fluorophenoxy)quinolones 12a–e were synthesized through an eight‐step reaction starting from commercially available 1‐(4‐hydroxy‐3‐methoxyphenyl)‐ethanone which has been illustrated in detail in our previous study .…”

“…The c‐Met inhibitors undergoing clinical trials or launched suggested that quinoline pharmacophores were essential for furnishing hydrogen bonds with the backbone of c‐Met kinase, and the aryl fragment (moiety B) probably generated hydrophobic binds. Importantly, there should be two structural characteristics on the linkage (moiety C) between moiety A and B, one is 5‐atoms regulation and the other is possessing hydrogen‐bond donors or acceptors simultaneously . In our previous studies, a variety of pharmacodynamics skeletons were introduced as the linker, which resulted in various derivatives 6–10 (Fig.…”

“…In our previous studies, a variety of pharmacodynamics skeletons were introduced as the linker, which resulted in various derivatives 6–10 (Fig. ) with excellent c‐Met inhibition potency .…”

Design, Synthesis, and Biological Evaluation of 4‐Phenoxyquinoline Derivatives Containing Benzo[d]thiazole‐2‐yl Urea as c‐Met Kinase Inhibitors

“…As shown in Scheme , the key intermediate 3‐fluoro‐4‐(6‐methoxy‐7‐((3‐substituted aminopropyl)oxy)quinolin‐4‐yloxy)aniline ( 20a – d ) was prepared from acetovanillone which was claimed in detail in our previous study .…”

A rapid and sensitive LC‐MS/MS method for evaluation of the absolute oral bioavailability of a novel c‐Met tyrosine kinase inhibitor QBH‐196 in rats

“…Furthermore, a lot of new small molecule inhibitors have emerged, such as Foretinib, BMS-777607, SGX-523 and Cabozatinib (Logan, 2013;Sharma et al, 2013;Buchanan et al, 2009;Karras et al, 2013), some of which are at a clinical trial stage and some have even been launched (Albrecht et al, 2008). , N 1 -(3-fluoro-4-{6-methoxy-7-[3-(4-methylpiperidin-1-yl) propoxy] quinolin-4-yloxy}phenyl)-N4-(2,4-difulurobenzylidene) semicarbazided, is a selective quinoline-based multitarget c-Met kinase inhibitor (Qi et al, 2013a(Qi et al, , 2013b) that exhibits significant cytotoxicity against a number of cancer cell lines in vitro, such as HT-29, MKN-45, MDA-MB-231 and A549 cells (Qi et al, 2013a(Qi et al, , 2013b. Compared with Foretinib, it increased by 48.4-, 3.6-, 2.1-and 3.3-fold the cytotoxic activity against U87MG, NCI-H460, A549 and HT-29 cell lines, respectively (Qi et al, 2013a(Qi et al, , 2013b.…”