Rational design, synthesis, and evaluation of nanomolar type II dehydroquinase inhibitors

The in silico design, synthesis, and biological evaluation of ten potent type II dehydroquinase inhibitors are described. These compounds contain an anhydroquinate core, incorporated as a mimic of the enolate reaction intermediate. This substructure is attached by a variety of linking units to a terminal phenyl group that binds in an adjacent pocket. Inhibitors were synthesised from (-)-quinic acid using palladium-catalysed Stille and carboamidation chemistry. Several inhibitors exhibited nanomolar inhibition constants against type II dehydroquinases from Streptomyces coelicolor and Mycobacterium tuberculosis. These are among the most potent inhibitors of these enzymes reported to date.     

EGFR(T790M)抑制剂的设计、合成及活性评价

表皮生长因子受体(EGFR)的T790M突变最为频发,也是肺癌临床治疗失败的主要原因之一。鉴于先导化合物B6优良的抗H1975细胞系和异植瘤活性,对其进行了EGFR(T790M)激酶抑制活性的确认,并使用Autodock软件确认了两者的相互作用。以EGFR(T790M)为靶点对B6进行定向结构修饰,所得目标化合物经NMR和MS表征后,联合体外激酶、细胞生物活性与Autodock软件解释它们的构效关系。结果表明,3-(苯并[d][1,3]二氧杂-5-基)-1-(1-(乙烯基磺酰基)哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺的抗H1975细胞增殖活性(IC₅₀=(1.16±0.24)μmol/L)与B6(IC₅₀=(0.91±0.36)μmol/L)相似,尽管其对EGFR(T790M)的抑制活性(IC₅₀=(148.2±7.2)nmol/L)不如B6(IC₅₀=(22.0±2.6)nmol/L)。以7H-吡咯并[2,3-d]嘧啶-4-胺为母核,取代基分别为胡椒环基和4-取代哌啶基者可开发活性更优的EGFR(T790M)抑制剂,指导后期研究。     

不同饱和烃对变压器油性能影响研究

考察了不同饱和烃对变压器油电气性能、抗氧化性能、溶解性能、抗析气性能和热物性的影响。结果表明,不同饱和烃的电气性能、热物性、抗析气性能、抗氧化性能及对抗氧剂的感受性相当,但环烷烃具有优异的溶解性能,是变压器油的理想组分。     

某高砷银铅锌矿降砷试验研究

对内蒙古某高砷银铅锌矿石,采用全优先浮选工艺流程,通过对组合抑制剂交互作用、协同效应的试验研究,确定采用石灰+组合抑制剂SSCH抑砷。闭路试验获得铅精矿含铅50.06%、含银2 040.35 g/t、含砷0.442%、铅回收率91.62%、银回收率72.34%和锌精矿含锌46.81%、含砷0.486%、锌回收率82.04%的良好指标。     

De Novo Design,Synthesis and Evaluation of Benzylpiperazine Derivatives as Highly Selective Binders of Mcl‐1

Considerable efforts have been made to the development of small‐molecule inhibitors of antiapoptotic B‐cell lymphoma 2 (Bcl‐2) family proteins (such as Bcl‐2, Bcl‐x_L, and Mcl‐1) as a new class of anticancer therapies. Unlike general inhibitors of the entire family, selective inhibitors of each member protein can hopefully reduce the adverse side effects in chemotherapy treatments of cancers overexpressing different Bcl‐2 family proteins. In this study, we designed four series of benzylpiperazine derivatives as plausible Bcl‐2 inhibitors based on the outcomes of a computational algorithm. A total of 81 compounds were synthesized, and their binding affinities to Bcl‐2, Bcl‐x_L, and Mcl‐1 measured. Encouragingly, 22 compounds exhibited binding affinities in the micromolar range (K_i<20 μM ) to at least one target protein. Moreover, some compounds were observed to be highly selective binders to Mcl‐1 with no detectable binding to Bcl‐2 or Bcl‐x_L, among which the most potent one has a K_i value of 0.18 μM for Mcl‐1. Binding modes of four selected compounds to Mcl‐1 and Bcl‐x_L were derived through molecular docking and molecular dynamics simulations. It seems that the binding affinity and selectivity of these compounds can be reasonably interpreted with these models. Our study demonstrated the possibility for obtaining selective Mcl‐1 inhibitors with relatively simple chemical scaffolds. The active compounds identified by us could be used as lead compounds for developing even more potent selective Mcl‐1 inhibitors with potential pharmaceutical applications.     

A Conformational Mimetic Approach for the Synthesis of Carbocyclic Nucleosides as Anti‐HCV Leads

Computer‐aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti‐hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6‐amino‐1H‐pyrazolo[3,4‐d]pyrimidine (6‐APP)‐based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA‐dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6‐APP analogues were prepared and evaluated for anti‐HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC₅₀ value of 6.6 μM as a preliminary anti‐HCV lead.     

Hydrosoluble Benzo[e]pyridoindolones as Potent Inhibitors of Aurora Kinases

Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy. We identified benzo[e]pyridoindoles (BePI) as powerful aurora kinase inhibitors. Their efficiency was demonstrated both in enzymatic inhibition studies and in cell culture assays. New BePI molecules were synthesized, and a structure–activity relationship study was conducted with the aim of improving the activity and solubility of the lead compound. Tetracyclic BePI derivatives are characterized by a particular curved shape, and the presence of an oxo group on the pyridine ring was found to be required for aurora kinase B inhibition. New hydrosoluble benzo[e]pyridoindolones were subsequently designed, and their efficacy was tested by a combination of cell‐cycle analysis and time‐lapse experiments in live cells. The most active BePI derivative, 13 b , inhibited the cell cycle, drove cells to polyploidy, and eventually induced apoptosis. It exhibited high antiproliferative activity in HeLa cells with an IC₅₀ value of 63 nM . Relative to compounds tested in clinical trials, this antiproliferative potency places 13 b among the top 10 aurora kinase inhibitors. Our results justify further in vivo evaluation in preclinical animal models of cancer.