40172-95-0Relevant articles and documents
Development of novel human lactate dehydrogenase A inhibitors: High-throughput screening, synthesis, and biological evaluations
Zhou, Yuan,Tao, Pingde,Wang, Meigui,Xu, Peng,Lu, Wei,Lei, Pan,You, Qiuyun
, p. 105 - 115 (2019)
Human lactate dehydrogenase A (LDHA) plays a critical role in the glycolytic process, making the enzyme an ideal of anti-cancer drug target. Herein, we report the discovery of novel potent LDHA inhibitors by screening an in-house library. The hit-to-lead modification enabled us to identify compound 24c, which inhibited LDHA activity with an EC50 value of 90 nM, and reduced MiaPaCa-2 cancer cell proliferation with an IC50 value of 2.1 μM. In line with the in vitro anticancer activity, 24c suppressed the tumor growth at a dose of 10 mg/kg in a MiaPaCa-2 cells xenograft model, but with little effect to the mice weight. Moreover, 24c strongly inhibited MiaPaCa-2 cell colonies formation, induced MiaPaCa-2 cell apoptosis, and arrested MiaPaCa-2 cell cycle at G2 phase. In addition, the mitochondrial bioenergetics analysis suggested that 24c could reprogram cancer cell metabolic pathways from glycolysis to oxidation phosphorylation, which verified by decreasing the extracellular acidification rates and lactate formation, and increasing oxygen consumption rate in cancer cell. All these results indicate 24c is a promising metabolic modulator for the anticancer drug development.
Reactions of 4-Nitrophenyl 5-substituted Furan-2-carboxylates with R2NH/R2NH2+ in 20 mol% DMSO(aq): Effect of Aryl Group on the Acyl-Transfer Reaction
Pyun, Sang Yong,Paik, Kyu Cheol,Han, Man So,Cho, Bong Rae
supporting information, p. 994 - 1000 (2021/05/11)
Reactions of 4-nitrophenyl 2-furoates (1a–e) with R2NH/R2NH2+ in 20 mol% DMSO(aq) have been studied. The reactions produced aminolysis products and exhibited second-order kinetics. The Br?nsted plots were linear with βnuc values of 0.75–0.89, which remained nearly the same for all 5-furyl substituents. The rate data showed excellent correlations on the Yukawa-Tsuno plots with ρ(x)?=?0.72–1.1, and r?=?0.55–0.95, respectively. The ρ value increased and r value decreased with a stronger nucleophile, indicating an increase in the electron density at the C-O bond and a decrease in the resonance contribution. The results have been interpreted with the addition–elimination mechanism in which the second step is the rds. By comparing with the data for ArC(O)OC6H4-4-NO2 (Ar?=?Ph, thienyl), the effect of the aryl group on the acyl transfer reaction was assessed.
Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer
Long, Huan,Hu, Xiaolong,Wang, Baolin,Wang, Quan,Wang, Rong,Liu, Shumeng,Xiong, Fei,Jiang, Zhenzhou,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
, p. 12089 - 12108 (2021/09/06)
Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.