Abstract
In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 μM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation.
Highlights
Nowadays, cancer has still been the leading cause of human death worldwide and has become a major public health problem
The target compounds were synthesised according to the procedure reported earlier[34] as outlined in Scheme 1
Through Friedlander synthesis, compound 2 was further reacted with different o-aminobenzaldehyde under nitrogen atmosphere to afford the corresponding quinoline derivatives 3a–d in 62 $ 68% yields
Summary
Cancer has still been the leading cause of human death worldwide and has become a major public health problem. Development of small molecular drugs specially targeting the key proteins in the signalling pathways relevant to tumourigenesis and tumour growth may provide opportunities to find new targeted anticancer agents with significantly improved therapeutic index. The signalling pathway offers attractive targets for the development of anticancer agents Among this signalling pathway, the Ser/Thr kinases MEK1/2 have been attracting special interests because the kinases phosphorylate and activate ERK1/2. FDA recently approved the combination of dabrafenib and trametinib for the treatment of BRAFmutant metastatic melanoma, NSCLC, and anaplastic thyroid cancer[19] These examples have highlighted the potential of MEK inhibitors as novel anticancer agents. Recent studies have pointed out that some 1,3,4-oxadiazole derivatives showed potent anticancer activity through inhibiting various targets, such as telomerase, histone deacetylase (HDAC), glycogen synthase kinase-3 (GSK), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF)[29,30]. In continuation of our research on the novel UA derivatives with anticancer properties[34], a series of novel UA derivatives bearing quinoline, oxadiazole, and thiadiazole moieties were designed and synthesised, and their anticancer activities and possible mechanisms of action were investigated and presented
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