Design and Efficient Synthesis of RalA Inhibitors Containing the Dihydro‐α‐carboline Scaffold
Hai‐Jun Leng, Yuting Wang, Xiang‐Hong He, Houlin Xia, Peng‐Shuai Xu, Peng Xiang, Qingqing He, Gu Zhan, Wei Huang
Abstract
Abstract Ras‐related protein RalA is a member of the Ras small GTPases superfamily. Its activation plays an important role in regulating tumor initiation, invasion, migration, and metastasis. In this study, we designed a new type of RalA inhibitor containing a dihydro‐α‐carboline scaffold. The structurally new dihydro‐α‐carboline derivatives could be efficiently synthesized in good yields through a newly developed three‐component [3+2+1] cyclization reaction. Evaluation of the biological activity showed that some of the dihydro‐α‐carboline derivatives can inhibit RalA/B and proliferative activities of NSCLC cell lines. The 4‐(pyridin‐3‐yl)‐dihydro‐α‐carboline compound ( 3 o ) was found to be the most potent derivative, with IC 50 values of 0.43±0.03, 0.64±0.07, 0.93±0.10, and 1.54±0.15 μM against A549, H1299, H460, and H1975 cells, respectively. Mechanism investigation suggested that 3 o inhibits the RalA/B activation of A549, down‐regulates Bcl‐2, stimulates cytochrome c and PARP cleavage, and induces cell apoptosis. A molecular docking study revealed that 3 o can form stable hydrogen bonds with residues of RalA. Moreover, amide‐π and alkyl‐π interactions also contributed to the affinity between 3 o and RalA.