Exploration of acridine scaffold as a potentially interesting scaffold for discovering novel multi-target VEGFR-2 and Src kinase inhibitors

• Published in: Bioorganic & medicinal chemistry 2011-06, Vol.19 (11), p.3312-3319
• Main Authors: Luan, Xudong, Gao, Chunmei, Zhang, Nannan, Chen, Yuzong, Sun, Qinsheng, Tan, Chunyan, Liu, Hongxia, Jin, Yibao, Jiang, Yuyang
• Format: Article
• Language: English
• Subjects: Acridine; Acridines - chemical synthesis; Acridines - chemistry; Acridines - toxicity; Aminoacridines - chemical synthesis; Aminoacridines - chemistry; Aminoacridines - pharmacology; Antineoplastic agents; Antiproliferative activity; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Computer Simulation; General aspects; Humans; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Multi-target; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - toxicity; Src; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR-2
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.04.053

A series of 21 acridine derivatives have been discovered and synthesized as potent VEGFR-2 and Src inhibitors. VEGFR-2 and Src kinases both play important roles in cancers. In certain cancers, Src works synergistically with VEGFR-2 to promote its activation. Development of multi-target drugs against VEGFR-2 and Src is of therapeutic advantage against these cancers. By using molecular docking and SVM virtual screening methods and based on subsequent synthesis and bioassay studies, we identified 9-aminoacridine derivatives with an acridine scaffold as potentially interesting novel dual VEGFR-2 and Src inhibitors. The acridine scaffold has been historically used for deriving topoisomerase inhibitors, but has not been found in existing VEGFR-2 inhibitors and Src inhibitors. A series of 21 acridine derivatives were synthesized and evaluated for their antiproliferative activities against K562, HepG-2, and MCF-7 cells. Some of these compounds showed better activities against K562 cells in vitro than imatinib. The structure–activity relationships (SAR) of these compounds were analyzed. One of the compounds ( 7r) showed low μM activity against K562 and HepG-2 cancer cell-lines, and inhibited VEGFR-2 and Src at inhibition rates of 44% and 8% at 50 μM, respectively, without inhibition of topoisomerase. Moreover, 10 μM compound 7r could reduce the levels of activated ERK1/2 in a time dependant manner, a downstream effector of both VEGFR-2 and Src. Our study suggested that acridine scaffold is a potentially interesting scaffold for developing novel multi-target kinase inhibitors such as VEGFR-2 and Src dual inhibitors.