Synthesis and evaluation of 4-Anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade

• Published in: Bioorganic & medicinal chemistry letters 2003-09, Vol.13 (18), p.3031-3034
• Main Authors: Berger, Dan, Dutia, Minu, Powell, Dennis, Wu, Biqi, Wissner, Allan, Boschelli, Diane H., Floyd, M.Brawner, Zhang, Nan, Torres, Nancy, Levin, Jeremy, Du, Xuemei, Wojciechowicz, Donald, Discafani, Carolyn, Kohler, Constance, Kim, Steven C., Feldberg, Larry R., Collins, Karen, Mallon, Robert
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Division - drug effects; Cell Line, Tumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; MAP Kinase Kinase 1; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Neoplasms, Experimental - drug therapy; Nitriles - chemical synthesis; Nitriles - pharmacology; Quinolines - chemical synthesis; Quinolines - pharmacology; Signal Transduction - drug effects; Structure-Activity Relationship; Transplantation, Heterologous; Treatment Outcome
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00640-1

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile ( 3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure–activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade. A series of 4-anilino-3-quinolinecarbonitriles was synthesized and evaluated against kinases of the Ras-MAPK signaling cascade.