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
, 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.
Synthesis and evaluation of 2-(4-[4-acetylpiperazine-1-carbonyl] phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives as potential PARP-1 inhibitors and preliminary study on structure-activity relationship
Cao, Xuan,Chen, Miaojia,Huang, Honglin,Jiang, Lizhi,Li, Yang,Liu, Yunfan,Peng, Junmei,Tang, Guotao,Wu, Kaiyue
, (2021/06/25)
Although 1H-benzo[d]imidazole-4-carboxamide derivatives have been explored for a long time, the structure–activity relationship of the substituents in the hydrophobic pocket (AD binding sites) has not thoroughly discovered. Here in, a series of 2-(4-[4-acetylpiperazine-1-carbonyl]phenyl)-1H-benzo[d]imidazole-4-carboxamide derivatives have been designed, synthesized, and successful characterization as novel and effective poly ADP-ribose polymerases (PARP)-1 inhibitors to improve the structure–activity relationships about the substituents in the hydrophobic pocket. These derivatives were evaluated for their PARP-1 inhibitory activity and cellular inhibitory against BRCA-1 deficient cells (MDA-MB-436) and wild cells (MCF-7) using PARP kit assay and MTT method. The results indicated that compared with other heterocyclic compounds, furan ring-substituted derivatives 14n-14q showed better PARP-1 inhibitory activity. Among this derivatives, compound 14p displayed the strongest inhibitory effects on PARP-1 enzyme (IC50?=?0.023 μM), which was close to that of Olaparib. 14p (IC50?=?43.56 ± 0.69 μM) and 14q (IC50?=?36.69 ± 0.83 μM) displayed good antiproliferation activity on MDA-MB-436 cells and inactivity on MCF-7 cells, indicating that 14p and 14q have high selectivity and targeting. The molecular docking method was used to explore the binding mode of compound 14p and PARP-1, and implied that the formation of hydrogen bond was essential for PARP-1 inhibition activities. This study also showed that in the hydrophobic pocket (AD binding sites), the introduction of strong electronegative groups (furan ring, e.g.) or halogen atoms in the side chain of benzimidazole might improve its inhibitory activity and this strategy could be applied in further research.
