State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China.
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, 610052, Chengdu, China.
ChemMedChem. 2021 Mar 3;16(5):851-859. doi: 10.1002/cmdc.202000722. Epub 2020 Nov 27.
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 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.
Ras 相关蛋白 RalA 是 Ras 小分子 GTPases 超家族的成员。其激活在调节肿瘤起始、侵袭、迁移和转移中起着重要作用。在这项研究中，我们设计了一种新型的含有二氢-α-咔啉支架的 RalA 抑制剂。通过新开发的三组分 [3+2+1] 环化反应，可以有效地以良好的产率合成结构新颖的二氢-α-咔啉衍生物。生物活性评价表明，一些二氢-α-咔啉衍生物可以抑制 RalA/B 和非小细胞肺癌细胞系的增殖活性。发现 4-(吡啶-3-基)-二氢-α-咔啉化合物 (3o) 是最有效的衍生物，对 A549、H1299、H460 和 H1975 细胞的 IC 值分别为 0.43±0.03、0.64±0.07、0.93±0.10 和 1.54±0.15 μM。机制研究表明，3o 抑制 A549 中的 RalA/B 激活，下调 Bcl-2，刺激细胞色素 c 和 PARP 切割，并诱导细胞凋亡。分子对接研究表明，3o 可以与 RalA 的残基形成稳定的氢键。此外，酰胺-π 和烷基-π 相互作用也有助于 3o 和 RalA 之间的亲和力。
