The Computer-Aided Design,Synthesis, and Activity Prediction of New Leucine Aminopeptidase Inhibitors

The design, stereo-, and enantioselective synthesis and activity prediction of aminophosphonic acids as new leucine aminopeptidase inhibitors will be discussed.     

Design,Synthesis, and Biological Evaluation of Quercetagetin Analogues as JNK1 Inhibitors

The recent discovery of c‐Jun NH₂‐terminal kinase JNK1 suppression by natural quercetagetin ( 1 ) is a promising lead for the development of novel anticancer agents. Using both X‐ray structure and docking analyses we predicted that 5′‐hydroxy‐ ( 2 ) and 5′‐hydroxymethyl‐quercetagetin ( 3 ) would inhibit JNK1 more actively than the parent compound 1 . Notably, our drug design was based on the active enzyme–ligand complex as opposed to the enzyme’s relatively open apo structure. In this paper we test our theoretical predictions, aided by docking‐model experiments, and report the first synthesis and biological evaluation of quercetagetin analogues 2 and 3 . As calculated, both compounds strongly suppress JNK1 activity. The IC₅₀ values were determined to be 3.4 μM and 12.2 μM , respectively, which shows that 2 surpasses the potency of the parent compound 1 (IC₅₀=4.6 μM ). Compound 2 was also shown to suppress matrix metalloproteinase‐1 expression with high specificity after UV irradiation.     

基于结构的新型CDK7抑制剂的设计、合成及其抗肿瘤活性

根据细胞周期依赖性激酶7(CDK7)的蛋白结构, 利用Discovery Studio 2.1程序包中的LigandFit模块建立了CDK7抑制剂的分子对接模型, 采用受试者工作特征曲线(ROC)方法选择LigScore2为最佳打分函数(ROC曲线下的面积为0.95), 并验证了该模型的准确性. 利用该模型对设计的化合物与CDK7蛋白进行对接分析, 得到了2个打分最高的化合物16、17, 进而通过13步的合成路线, 以中等至高的收率得到目标化合物, 并测定其体外抗肿瘤活性. 结果表明, 所合成的化合物对急性前髓细胞性白血病细胞(HL60)、鼻咽癌细胞(KB)、肝肿瘤细胞(SMMC-7721)、结肠腺癌细胞(HCT-116)、肺癌细胞(A549)细胞株均有抑制作用(IC50值为0.84-19.70 μmol·L-1), 其中化合物16对HL60细胞株的IC50值最低, 为0.84 μmol·L-1.     

The Rational Design of Drugs with Phos-phonic/phinic Acids as Enzyme Inhibitors Isosteric Receptor Ligands

Phosphonic/phosphinic acid analogs have been studied for inhibitory and ligand activity in farnesyl pyrophosphate synthase, prostaglandin, and other GPCR's.     

Design,Synthesis and Biological Evaluation of Sulfenimine Cephalosporin Analogues as β-Lactamase Inhibitors

A series of sulfenimine cephalosporin derivatives(6a-6t) was designed, synthesized and evaluated for their inhibitory activity against class A β-lactamase(TEM-1) derived from E. coli, and class C β-lactamase (cephalosporinase) derived from wild Bacillus subtilis in cell-free systems. Most of the tested compounds showed enhanced inhibitory activity against class C β-lactamase(cephalosporinase) compared with tazobactam. The most promising compounds 6c and 6o in combination with cefradine(IC₅₀=1.80 and 1.59 μmol/L, respectively) were further investigated against a series of clinical isolated β-lactamase-producing bacterial strains. The results reveal that compounds 6c and 6o in combination with cefradine show two to four times more activity than cefradine alone against methicillin-sensitive Staphylococcus aureus(MSSA) and Klebsiella pneumoniae. The data suggest that the sulfenimine moiety may be beneficial to the activity and selectivity of inhibitors.     

Rational Design,Synthesis and Evaluation of Oxazolo[4,5-c]-quinolinone Analogs as Novel Interleukin-33 Inhibitors

Interleukin-33 (IL-33) is an epithelial-derived cytokine that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. Although IL-33 is considered a potential target for the treatment of allergy-related diseases, no small molecule that inhibits IL-33 has been reported. Based on the structure-activity relationship and in vitro 2D NMR studies employing ¹⁵N-labeled IL-33, we identified that the oxazolo[4,5-c]-quinolinone analog 7 c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7 c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7 c is the first low molecular weight IL-33 inhibitor and may be used as a prototype molecule for structural optimization and investigation of the IL-33/ST2 signaling pathway.     

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Development of heat shock protein 90 (Hsp90) C‐terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.     

Flexible Enantiodivergent Synthesis and Biological Activity of Mannostatin Analogues, New Cyclitol Glycosidase Inhibitors

Mannostatin A (1) is a new cyclitol inhibitor of glycoprotein processing. 2-Epimannostatin A (12) and its enantiomer (13) as well as their positional isomers (14, 15) were designed for probing structure-activity relationships in this class of glycosidase inhibitors. The analogues have been synthesized from (S)-4-((tert-butyldimethylsilyl)oxy)-2-cyclopentenone by an enantiodivergent strategy in a totally stereospecific fashion. Compound 13 showed inhibition against almond beta-glucosidase and is shown to be a topographical analogue of beta-D-glucopyranoside.     

烟酰胺腺嘌呤二核苷酸类CD38抑制剂的合成及生物活性评价

分别以1,3,5-三苯甲酰基-α-D-核糖、3,5-二苯甲酰基-2-脱氧-2,2-氟戊呋喃糖-1-酮和D-木糖为原料,经由烟酰胺核苷及烟酰胺核苷酸中间体,合成了系列糖环经氟原子取代的烟酰胺腺嘌呤二核苷酸(NAD)类CD38抑制剂.基于对CD38的水解抑制能力的考察,评价了所合成氟代NAD类似物的活性.结果表明,糖环上氟原子取代的数目和位置对抑制剂活性的影响十分明显,烟酰胺核苷的端基构型对活性的影响较大.2个化合物均显示出非常好的CD38抑制活性,其中化合物2a的抑制活性高出阳性对照物阿糖型氟代烟酰胺腺嘌呤二核苷酸2个数量级.     

Design,Synthesis and SAR Studies of Novel and Potent Dipeptidyl Peptidase 4 Inhibitors

Dipeptidyl peptidase 4 (DPP‐4) is a clinically validated target for the treatment of type 2 diabetes mellitus (T2DM). To discover novel and potent DPP‐4 inhibitors, three series of compounds were designed and synthesized in this study based on our previously identified novel scaffold of 2‐phenyl‐3,4‐dihydro‐2H‐benzo[f]chromen‐3‐amine. Among the designed compounds, 41d‐1 was the most potent one with an IC₅₀ value of 16.00 nM. Besides, 41d‐1 (5 mg/kg) displayed a moderate glucose tolerance capability in ICR mice. Structure‐activity‐relationship (SAR) studies were discussed in detail, which is constructive for our further optimization.     

Structure-Based Bioisosterism Design,Synthesis, Biological Activity and Toxicity of 1,2,4-Oxadiazole Substituted Benzamides Analogues Containing Pyrazole Rings

In order to discover pesticidal lead compounds with high activity and low toxicity, a series of novel benzamides substituted with pyrazole-linked 1,2,4-oxadiazole were designed via bioisosterism. The chemical structures of the target compounds were confirmed via ¹H NMR, ¹³C NMR and HRMS analysis. The preliminary bioassay showed that most compounds exhibited good lethal activities against Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis and Spodoptera frugiperda at 500 mg/L. Particularly in the case of Mythimna separate, compound 14q (70%) exhibited obvious insecticidal activity. In addition, compound 14h demonstrated good fungicidal activity against Pyricularia oryae with an inhibition rate of 77.8%, and compounds 14e, 14k, 14n and 14r also showed certain antifungal activities (55.6–66.7%). The zebrafish toxicity test showed that the LC₅₀ of compound 14h was 14.01 mg/L, which indicated that it may be used as a potential leading compound for further structural optimization.     

Design and Synthesis of Muramyl Dipeptide Cyclic Analogue

A new conformationalloy restricted cyclic analogue of muramyl dipeptide was designed and manually synthesized by our “Meshed-Bag Gathered-Bunch” method with a combination of Fmoc,ally and N-1-(4,4-dimethyl-2,6-dioxocyclo-hexylidene) ethyl chemical protection strategy.     

Design and Enantioselective Synthesis of Phosphonates as Enzyme Inhibitors

Abstract

The serine proteases [1] form an important group of hydrolytic enzymes essential to a variety of biological activities ranging from food digestion to blood clotting. However their uncontrolled activity is also known to be implicated in a number of pathological conditions including emphysema, cystic fibrosis, cancer and myocardial infarction. Their selective control is therefore an important goal and could offer a basis for the rational design of therapeutic agents.     

Use of Statistical Mixture Designs to Evaluate Ternary Mixtures of Organics as Corrosion Inhibitors

Abstract

Corrosion inhibitors are often mixtures of compounds which may or may not behave as a linear comination of the pure components in the mixture. Evaluation of the effect of the composition of the mixture on its inhibitory properties are often done on fragmentary data and there is an incomplete knowledge of the system being studied. Mixture Designs can be used to plan experiments which provide equations to model the system being studied.     

基于药效团模型设计合成新型ALS抑制剂

以ALS抑制剂药效团模型为基础建立了提问结构,将药效团模型中的生物结构信息输入到多种小分子三维结构数据库(NCI-3D和ACD-3D数据库)中,分别搜寻出100多个符合特征结构信息的全新结构候选化合物.以这些命中结构的分子特征信息为基础设计合成了一系列新型的ALS抑制剂,初步生物活性测试结果表明,预期有生物活性的化合物显示出一定的ALS酶抑制剂活性.     

Design,Synthesis, and Biochemical Evaluation of New Triazole Derivatives as Aurora-A Kinase Inhibitors

Aurora-A kinase, a key mitosis regulator, is expressed in a cell cycle-dependent manner and has an essential role in maintaining chromosomal stability and the normal progression of the cell through mitosis. Aurora-A kinase is overexpressed in many malignant solid tumors, such as breast, ovarian, colon, and pancreatic cancers. Thus, inhibiting Aurora-A kinase activity is a promising approach for cancer treatment. Here, new triazole derivatives were designed as bioisosteric analogues of the known inhibitor JNJ-7706621. The new compounds showed interesting inhibitory activity against Aurora-A kinase, as attested by IC₅₀s in the low to submicromolar range.     

新型噻唑-肉桂酸杂合体的设计、合成及黄嘌呤氧化酶抑制活性

以乙酰乙酸乙酯和苯甲醛为原料,经5步反应得到14个2-取代肉桂酰胺基-4-甲基噻唑-5-羧酸化合物,其结构均经¹H-NMR,¹³C-NMR和MS确证。经初步体外黄嘌呤氧化酶抑制活性评价,化合物5l表现出对黄嘌呤氧化酶有一定的抑制作用,抑制率为64.91%。      

Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches

Targeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of Mycobacterium tuberculosis (Mtb) is a complex of three layers, one of which is Peptidoglycan, an essential component providing rigidity and strength. UDP-GlcNAc, a precursor for the synthesis of peptidoglycan, is formed by GlmU, a bi-functional enzyme. Inhibiting GlmU Uridyltransferase activity has been proven to be an effective anti-bacterial, but its similarity with human enzymes has been a deterrent to drug development. To develop Mtb selective hits, the Mtb GlmU substrate binding pocket was compared with structurally similar human enzymes to identify selectivity determining factors. Substrate binding pockets and conformational changes upon substrate binding were analyzed and MD simulations with substrates were performed to quantify crucial interactions to develop critical pharmacophore features. Thereafter, two strategies were applied to propose potent and selective bacterial GlmU Uridyltransferase domain inhibitors: (i) optimization of existing inhibitors, and (ii) identification by virtual screening. The binding modes of hits identified from virtual screening and ligand growing approaches were evaluated further for their ability to retain stable contacts within the pocket during 20 ns MD simulations. Hits that are predicted to be more potent than existing inhibitors and selective against human homologues could be of great interest for rejuvenating drug discovery efforts towards targeting the Mtb cell wall for antibacterial discovery.