Background: Thienopyrimidinone is a newly designed, selective fibroblast growth factor receptor 1 (FGFR1) inhibitor with an excellent anticancer effect. Objective: The goal of the present study was to design and synthesize better FGFR1 inhibitors through modifications of the lead
compound thienopyrimidinone. Methods: In the present study, a series of C-2 substituted derivatives of thienopyrimidinone, namely L1-L16, were synthesized, and their inhibitory effects on FGFR1 were evaluated. The anti-proliferative activities of these compounds were assessed by MTT assay.
Results: Among the novel derivatives, L11 was found to exert remarkable FGFR1 inhibitory activity (79.93% at 10 μM) and anti-proliferative activity, with IC50 values of 2.1, 2.5, and 3.5 µM in the FGFR1-overexpressing cell lines, H460, HT-1197, and B16F10, respectively.
Conclusion: Our newly synthesized thienopyrimidinone derivatives may be candidate FGFR1 inhibitors for future development as novel anticancer agents.
Chuanmin Zhang,Shubiao Zhang,Defu Zhi,Yinan Zhao,Shaohui Cui,Jingnan Cui
This work designed a new delivery system (L-PTX-PSur), which could efficiently co-deliver paclitaxel (PTX) and survivin siRNA (Sur) to overcome the dose-limiting toxicity by effectively accumulating PTX in tumor and obtain enhanced therapy by synergistic effect. In this co-delivery system, protamine was selected to condense siRNA into a compacted ‘core’, and a carbamate-linked cationic lipid was used to develop PTX-loaded liposome to entrap the core. L-PTX-PSur with protamine could facilitate Sur entry into NCI-H460 cells and exhibited high encapsulation efficiency of PTX. In vitro studies on the NCI-H460 lung cancer cells revealed that L-PTX-PSur offered significant advantages over the control groups, and it had the highest cellular uptake, the lowest cell viability and the strongest apoptosis. Western blot result showed that survivin protein expression could be noticeably suppressed by L-PTX-PSur in NCI-H460 cells. And the down-regulation of survivin protein could lower the apoptotic threshold of cancer cells and render PTX more effective with low doses. Collectively, L-PTX-PSur with a low dose of PTX could induce a synergistic inhibitory effect on cancer cells growth by the collaboration of PTX and Sur. This work provides a promising strategy for the treatment of lung cancer.
ObjectiveTo synthesize a novel chalcone-1,3,4-thiadiazole hybrid and investigate its anticancer effects against NCI-H460 cells.Methods(E)-3-(4-bromophenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one, 1,3-dibromopropane and 1,3,4-thiadiazole-2-thiol were used as chemical materials to synthesize compound ZW97. The NCI-H460 lung cancer cell line was selected to explore the antitumor effects of compound ZW97 in vitro and in vivo.ResultsCompound ZW97 selectively inhibited cell proliferation against lung cancer cell lines NCI-H460, HCC-44 and NCI-H3122 with IC50 values of 0.15 μM, 2.06 μM and 1.17 μM, respectively. ZW97 suppressed migration and the epithelial–mesenchymal transition process in NCI-H460 cells in a concentration-dependent manner. Based on the kinase activity results and docking analysis, compound ZW97 is a novel tyrosine-protein kinase Met (c-Met kinase) inhibitor. It also inhibited NCI-H460 cell growth in xenograft models without obvious toxicity to normal tissues.ConclusionsCompound ZW97 is a potential c-Met inhibitor that might be a promising agent to treat lung cancer by inhibiting the epithelial–mesenchymal transition process.
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