In:
ChemMedChem, Wiley, Vol. 16, No. 5 ( 2021-03-03), p. 851-859
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.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.202000722
Language:
English
Publisher:
Wiley
Publication Date:
2021
detail.hit.zdb_id:
2209649-8
SSG:
15,3
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