Design, synthesis and biological evaluation of β-carboline derivatives as novel inhibitors targeting B-Raf kinase.
β-Carboline family of compounds is a large group of alkaloids widely distributed in nature and exhibits broad-spectrum anti-tumor activities. We designed and synthesized two series of novel 1-carboxamide- and 6-sulfonamide-substituted β-carboline derivatives 7a-p and 12a-b, and their wild type B-Raf kinase inhibitory activities were described. Most compounds showed moderate to excellent inhibitory activities. Among them, 1-carboxamide-6-(N-(3-(dimethylamino)propyl)-sulfamoyl)-β-carboline, 7e exhibited potent activity (IC(50)=1.62 μM), showing the potential for further investigation as a lead compound.
Laboratory of Molecular Design and Drug Discovery, School of Basic Sciences, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Botao
B
Xin
Weifang
W
Tang
Yue
Y
Wang
Guowu
G
Lin
Haichun
H
Liu
Yu
Y
Jiao
Yong
Y
Zhu
Haoliang
H
Yuan
Yadong
Y
Chen
Tao
T
Lu
D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002243:Carbolines; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf