Synthesis and Biological Evaluation of Indole‐2‐carbohydrazide Derivatives as Anticancer Agents with Anti‐angiogenic and Antiproliferative Activities

Abstract

A novel series of indole-2-carbohydrazide derivatives were synthesized, characterized, and evaluated for their antiproliferative activities against two cancer cell lines, HCT116 and SW480, and a normal human fetal lung fibroblast cell line, MRC-5. Among this series, compound 24 f displayed potent cytotoxic activities in vitro against HCT116 and SW480 cell lines with GI values of 8.1 and 7.9 μm, respectively, and was inactive against MRC-5 cells. The newly synthesized compounds were also evaluated for anti-angiogenesis capabilities by chick chorioallantoic membrane, human umbilical vein endothelial cell (HUVEC) migration, and endothelial microtubule formation assays. Moreover, the effects of 24 f on the vascular endothelial growth factor receptor-2 and the signaling pathway in HUVECs indicated that this compound inhibits VEGFR-2 and its downstream related proteins. These results indicate that compound 24 f, as well as the other derivatives, are promising inhibitors of angiogenesis.

Indole hydrazide compound ZJQ-24 inhibits angiogenesis and induces apoptosis cell death through abrogation of AKT/mTOR pathway in hepatocellular carcinoma

“…Although ZJQ-24 significantly downregulated the levels of p-VEGFR2 in HUVEC cells, the activity of VEGFR2 kinase was not prominent 23 . To clarify the functional role of ZJQ-24 in the antiangiogenic effect, we procceded to examine the interaction of ZJQ-24 with mTOR (PDB ID: 4JT6) and AKT(PDB ID: 3O96) proteins.…”

“…ZJQ-24 compound was identified and provided by the Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University) 23 . The compound was prepared as 100 mM stock solutions in DMSO and aliquots stored at −20 °C, protected from light.…”

“…Several recent reports demonstrated that dysregulated translation is omnipresent in human cancer 22 . In recent study, we originally synthesized a novel series of indole-2-carbohydrazide compounds as VEGFR2 tyrosine kinase inhibitor and evaluated for cytotoxicity in tumor cells and antiangiogenic effects in HUVECs 23 . However, the anti-hepatocellular carcinoma effects and functional mechanism of ZJQ-24, an active compound, remain unknown.…”

Discovery of 6‐Arylurea‐2‐arylbenzoxazole and 6‐Arylurea‐2‐arylbenzimidazole Derivatives as Angiogenesis Inhibitors: Design, Synthesis and in vitro Biological Evaluation

“…Recently,6-substituted benzoxazole or benzimidazole derivatives have been developed as multi-kinasei nhibitors, including tyrosine and serine/threonine kinases. [36] In the quest to find better anti-angiogenic agents, and as ac ontinuation of our previous studies on anticancer drug discovery, [66][67][68][69][70][71][72][73] we designed af amily of compoundsc ontaining 6-arylurea-2-arylbenzoxazoles and 6-arylurea-2-arylbenzimidazoles, with the goal of findingn ew potent anticancer agents ( Figure 2). [65] The X-ray crystallographic elucidation of the complex between 1 and VEGFR-2 demonstrated that the 2-fluoro-5-(trifluoromethyl)phenyl moiety is buried in the hydrophobic pocket, and the benzimidazole ring occupies the adenine pocket, interacting with the Cys919 residue, while the central arylurea linker is bent towardt he "hinge" region of the receptor.T herefore, we speculated that the length of the urea linker can be shortened appropriatelyt ob etter match the active site ( Figure 2).…”

“…Additionally,2 -arylbenzoxazole analogues exhibit av arietyo fb iological activities, especially antitumora ctivities, for example, compound CJM-126. [36] In the quest to find better anti-angiogenic agents, and as ac ontinuation of our previous studies on anticancer drug discovery, [66][67][68][69][70][71][72][73] we designed af amily of compoundsc ontaining 6-arylurea-2-arylbenzoxazoles and 6-arylurea-2-arylbenzimidazoles, with the goal of findingn ew potent anticancer agents ( Figure 2). Allthe synthesized compounds were evaluated in vitro for inhibition of H1975, A549, and HeLa cancer cell lines.…”