α—唑基—α—芳氧烷基频哪酮（芳乙酮）及其醇式衍生物的合成和生物活 …

对α－唑基－α－芳氧烷基频哪酮及其醇式衍生物的合成和生物生进行了研究，合成了３３个新型化合物，所有化合物的结构均经核磁共振和元素分析证实；初步的生物活性测试结果表明，该类化合物具有一定的杀菌活性和植物生长调节活性。     

α-唑基-α-芳氧烷基频哪酮(芳乙酮)及其醇式衍生物的合成和生物活性研究

对α－唑基－α－芳氧烷基频哪酮（芳乙酮）及其醇式衍生物的合成和生物活性进行了研究，合成了３３个新型化合物，所有化合物的结构均经核磁共振和元素分析证实；初步的生物活性测试结果表明，该类化合物具有一定的杀菌活性和植物生长调节活性．     

新型光系统II抑制剂的设计、合成和生物活性测定

根据药效团模型，合理设计并合成了新型光系统II(PSII)抑制剂化合物，进行 了元素分析和红外、紫外及核磁数据表征。希尔反应测试表明，亿合成的化合物均 具有抑制光系统II电子传递功能的生物活性，有的化合物活性较高，为新型PSII除 草剂的开发显示了广阔的应用前景。     

α—（1H—1,2,4—三唑—1—基）—α—芳氧烷基芳乙酮肟的合成和生物活性

对α－（１Ｈ－１，２，４－三唑－１－基）－α－芳氧烷基芳乙酮肟的合成和生物活性进行了研究，合成了１２个新型化合物，所有化合物的结构经１ＨＮＭＲ、ＭＳ和元素分析确证；初步生物活性测试结果表明，该类化合物具有一定的杀菌和植物生长调节活性．     

基于配体的组蛋白去乙酰化酶抑制剂的分子设计

本文采用Topomer Co MFA方法对39个组蛋白去乙酰化酶抑制剂进行了3D-QSAR研究,得到q~2=0. 877,r~2=0. 987的可靠模型。运用基于R基团搜索的Topomer Search技术对ZINC2015数据库进行了虚拟筛选,筛选出一批具有潜在活性的目标化合物,模型预测结果表明,筛选出的化合物活性比最初合成的化合物大幅度提高,其中筛选出的最高活性化合物S2-7(IC_(50)=0. 0235μmol·L~(-1))活性达到了最初合成的高活性化合物21(IC_(50)=0. 103μmol·L~(-1))的4倍。分子对接技术揭示了化合物结构和靶酶之间的联系,为更新型HDACIs的设计以及结构优化提供了重要信息和理论指导。     

Caspase-3抑制剂研究进展

Caspase-3是细胞凋亡的关键酶和执行者,研究开发Caspase-3抑制剂对于阐明许多重要疾病,提供治疗方案以及开发新型农药、兽药都具有潜在应用价值.通过计算机辅助分子设计、高通量筛选等先进方法技术,近来国内外发现了许多类型各异的高活性Caspase-3抑制剂,不少化合物活性达到了纳摩尔级.本文从合成肽类抑制剂、合成非肽类抑制剂、天然肽类抑制剂、天然非肽类抑制剂角度对近年来国内外Caspase-3抑制剂研究进展进行了综述,旨在为相关研究提供参考.     

苯并咪唑衍生物的合成及抗癌活性

为了获得具有抗癌活性的新型PARP抑制剂,以2-氨基-3-硝基苯甲酸为原料,通过酯化、硝基还原等反应合成了8个苯并咪唑衍生物。合成的中间体及目标化合物结构经过了核磁共振氢谱、碳谱、质谱的确证。计算机类药性评价和MTT实验表明,目标化合物具有良好的类药性质,其中化合物HSS04表现出了与阳性药相当的抗增殖活性。     

光系统II(PSII)抑制剂的比较分子场研究

以光系统II抑制剂DISCO(DIStance COmparisons)模型的活性构象分子作为模板,利用比较分子场分析方法对三类结构不同的化合物进行了三维构效关系的研究.研究结果有助于对DISCO重叠模型的评估和新型PSII抑制剂的设计与合成.     

1，5—苯并硫氮杂Zuo氯代β—内酰胺衍生物的合成、光谱及立体化学

苯并硫氮杂Zuo是一类具有重要生理活性的七元杂环化合物,近年来,通过亚胺双键（C＝N）的环加成反应向此类化合物分子中引入新的环系引起了它们的关注^[1-4]。这项工作对于合成新的杂Zuo类化合物从而筛选出具有特殊生理活性的物质有着重要意义。本文通过1,5－苯并硫氮杂Zuo与氯乙烯酮的反应向原分子中并合一个β－内酰胺活性单元,合成了一系列新型的1,5－苯并硫氮杂Zuo-α氯代－β－内酰胺衍生物（B1－B5）,研究了它们的波谱特征及立体结构。     

新型光系统II抑制剂的设计、合成和生物活性测定

根据药效团模型,合理设计并合成了新型光系统II(PSII)抑制剂化合物,进行 了元素分析和红外、紫外及核磁数据表征。希尔反应测试表明,亿合成的化合物均 具有抑制光系统II电子传递功能的生物活性,有的化合物活性较高,为新型PSII除 草剂的开发显示了广阔的应用前景。     

Kinetic properties of pancreatic and intestinal sPLA2 from chicken and mammals using the monomolecular film technique

The interfacial kinetic and binding data for the pancreatic and intestinal sPLA2 from bird and mammals show that these enzymes have dramatically different ability to bind and hydrolyse phospholipids. The main conclusions from our experimental data indicate that phosphatidylcholine monolayers (PC), in contrast to phosphatidylethanolamine (PE) and phosphatidylglycerol (PG), were resistant to the hydrolysis by human intestinal sPLA2. Conversely, chicken intestinal sPLA2 was found to be able to hydrolyse all the phospholipids tested, including PC. The experiments show also that the interfacial penetrating ability of chicken sPLA2 (from intestine and pancreas) was higher than their mammalian's orthologs. This observation is confirmed by the activity of pancreatic chicken PLA2 measured on PC film showing that the interfacial pressure window that permits sPLA2 activity was very large, between 5 and 20 dynes cm(-1), compared with the porcine pancreatic sPLA2-IB which was inactive at pressure above 15 dynes cm(-1). In trying to establish a structure-function relationship, we examined the surface electrostatic potentials of the various sPLA2 from chicken and mammals. We reported in this study that the binding, orientation and persistence of sPLA2 at the lipid-water interface is probably governed by the electrostatic and hydrophobic forces operative at this surface. These variations argue strongly that these enzymes are not isoforms and that they are expected to have functions other than the release of lipid mediators for the biosynthesis of the eicosanoids.     

Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design

The human secretory phospholipase A2 group IIA (PLA2-IIA) is a lipolytic enzyme. Its inhibition leads to a decrease in eicosanoids levels and, thereby, to reduced inflammation. Therefore, PLA2-IIA is of high pharmacological interest in treatment of chronic diseases such as asthma and rheumatoid arthritis. Quercetin and naringenin, amongst other flavonoids, are known for their anti-inflammatory activity by modulation of enzymes of the arachidonic acid cascade. However, the mechanism by which flavonoids inhibit Phospholipase A2 (PLA2) remained unclear so far. Flavonoids are widely produced in plant tissues and, thereby, suitable targets for pharmaceutical extractions and chemical syntheses. Our work focuses on understanding the binding modes of flavonoids to PLA2, their inhibition mechanism and the rationale to modify them to obtain potent and specific inhibitors. Our computational and experimental studies focused on a set of 24 compounds including natural flavonoids and naringenin-based derivatives. Experimental results on PLA2-inhibition showed good inhibitory activity for quercetin, kaempferol, and galangin, but relatively poor for naringenin. Several naringenin derivatives were synthesized and tested for affinity and inhibitory activity improvement. 6-(1,1-dimethylallyl)naringenin revealed comparable PLA2 inhibition to quercetin-like compounds. We characterized the binding mode of these compounds and the determinants for their affinity, selectivity, and inhibitory potency. Based on our results, we suggest C(6) as the most promising position of the flavonoid scaffold to introduce chemical modifications to improve affinity, selectivity, and inhibition of PLA2-IIA by flavonoids.     

A real-time fluorogenic phospholipase A(2) assay for biochemical and cellular activity measurements

A fluorogenic analog of the PLA(2) substrate PC, named Dabcyl-BODIPY-PC, or simply DBPC, was synthesized with a fluorescence quencher (Dabcyl, 4-[(4-[N,N-dimethylamino]phenyl)azo]benzoic acid) in the sn-1 acyl chain and a BODIPY fluor in the sn-2 acyl chain. DBPC was recognized by sPLA(2) from each of the four sources examined (bee venom, human synovial fluid, cobra venom, and bovine pancreas). A dramatic and quantifiable fluorescence enhancement of DBPC occurred upon phospholipase digestion both in the presence and absence of excess PC. Both real-time and endpoint assays for PLA(2) were sensitive, consistent, and rapid. Thus, DBPC can be used as a sensitive fluorogenic probe for in vitro high-throughput screening assays for PLA(2) activation and inhibition and would expedite studies of PLA(2) in cellular signaling, in vitro screening for drug discovery, and subcellular localization of enzyme activity.     

氧化剂存在下吡啶叶立德与1,4,4a,8a-四氢-1,4-桥亚甲基萘-5,8-二酮的反应

在[(Py)4Co(HCrO₄)₂]存在下,吡啶叶立德、喹啉叶立德或异喹啉叶立德分别和1,4,4a,8a-四氢-1,4-桥亚甲基萘-5,8-二酮反应,一步法合成了中氮茚类多环化合物(1a～1c,2a～2b,3).该方法原料易得,反应条件容易控制,为合成这类化合物提供了新方法.     

Synthesis of N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamides and their inhibitory activities against secretory phospholipase A₂

N-[2-(2,4-Difluorophenoxy)trifluoromethyl-3-pyridyl]sulfonamide derivatives 3-6 were prepared by the reaction of 3-pyridylamines and sulfonyl chlorides. Inhibitory activities of these compounds toward secretory phospholipase A? (sPLA?) were examined and N-[2-(2,4-difluorophenoxy)-5-trifluoromethyl-3-pyridyl]-2-naphthalenesulfonamide (5c) was found to be the most potent against sPLA? with an IC?? value of 90 μM.     

Secretory phospholipase A2 hydrolysis of phospholipid analogues is dependent on water accessibility to the active site

A new and unnatural type of phospholipids with the head group attached to the 2-position of the glycerol backbone has been synthesized and shown to be a good substrate for secretory phospholipase A2 (sPLA2). To investigate the unexpected sPLA2 activity, we have compared three different phospholipids by using fluorescence techniques and HPLC, namely: (R)-1,2-dipalmitoyl-glycero-3-phosphocholine (hereafter referred to as 1R), (R)-1-O-hexadecyl-2-palmitoyl-glycero-3-phoshocholine (2R), and (S)-1-O-hexadecyl-3-palmitoyl-glycero-2-phosphocholine (3S). Furthermore, to understand the underlying mechanisms for the observed differences, we have performed molecular dynamics simulations to clarify on a structural level the substrate specificity of sPLA2 toward phospholipid analogues with their head groups in the 2-position of the glycerol backbone. We have studied the lipids above 1R, 2R, and 3S as well as their enantiomers 1S, 2S, and 3R. In the simulations of sPLA2-1S and sPLA2-3R, structural distortion in the binding cleft induced by the phospholipids showed that these are not substrates for sPLA2. In the case of the phospholipids 1R, 2R, and 3S, our simulations revealed that the difference observed experimentally in sPLA2 activity might be caused by reduced access of water molecules to the active site. We have monitored the number of water molecules that enter the active site region for the different sPLA2-phospholipid complexes and found that the probability of a water molecule reaching the correct position such that hydrolysis can occur is reduced for the unnatural lipids. The relative water count follows 1R > 2R > 3S. This is in good agreement with experimental data that indicate the same trend for sPLA2 activity: 1R > 2R > 3S.     

A Biomimetic Nanoparticle to “Lure and Kill” Phospholipase A2

Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K-NP”). The L&K-NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in-coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K-NP structure, which voids toxicity associated with free molecules. In the study, L&K-NPs effectively inhibit PLA2-induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K-NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K-NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti-PLA2 approach.     

Inhibition of cPLA2 and sPLA2 activities in primary cultures of rat cortical neurons by Centella asiatica water extract

Leaf extract of Centella asiatica has been used as an alternative medicine for memory improvement in the Indian Ayurvedic system of medicine for a long time. Although several studies have revealed its effect in ameliorating the cognitive impairment in rat models of Alzheimer's disease, the molecular mechanism of C. asiatica on neuroprotection still remains unexplained. In this study, we investigated the effects of C. asiatica water extract on activity of subtypes of phospholipase A2 (PLA2) in primary cultures of rat cortical neurons and quantified by HPLC a possible molecule responsible for the activity. The cPLA2 and sPLA2 activities were inhibited in vitro by asiaticoside present in the water extract of C. asiatica. This extract may be a candidate for the treatment of neurodegenerative processes because of its pharmacological activity in the brain and its low toxicity, as attested by its long popular use as a natural product.     

A Biomimetic Nanoparticle to “Lure and Kill” Phospholipase A2

Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K‐NP”). The L&K‐NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in‐coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K‐NP structure, which voids toxicity associated with free molecules. In the study, L&K‐NPs effectively inhibit PLA2‐induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K‐NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K‐NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti‐PLA2 approach.     

Modulation of the pharmacological activities of secretory phospholipase A2 from Crotalus durissus cascavella induced by naringin

In this work we have characterized the action of the naringin, a flavonoid found in grapefruit and known for its various pharmacological effects, which include antioxidant blood lipid lowering and anticancer activity, on the structure and biochemical activities of a secretory phospholipase A (sPLA2) from Crotalus durissus cascavella, an important protein involved in the releasinge of arachidonic acid in phospholipid membranes. sPLA2 was incubated with naringin (mol:mol) at 37 °C and a discrete reduction in the UV scanning signal and a modification of the circular dichroism spectra were observed after treatment with naringin, suggesting modifications of the secondary structure of the protein. This flavonoid was able to decrease enzymatic activity and some pharmacological effects, such as myonecrosis, platelet aggregation, and neurotoxic activity caused by sPLA2, however, the inflammatory effect was not affected by naringin. In addition, small angle X-ray scattering (SAXS) data were collected for sPLA2 and naringin-treated sPLA2 to evaluate possible modifications of the protein structure. These structural investigations have shown that sPLA2 is an elongated dimer in solution and after treatment with naringin a conformational change in the dimeric configuration was observed. Our results suggest that structural modification may be correlated with the loss of enzymatic activity and alterations in pharmacological properties.