PTP1B抑制剂专利技术分析

蛋白酪氨酸磷酸酶1B(PTP1B)是治疗II型糖尿病的潜在的重要靶点,与肥胖、肿瘤也具有密切关系。本文以PTP1B抑制剂专利文献为基础,对其专利申请态势、地区分布、活跃度、重点申请人等进行了统计分析。     

CYP1B1抑制剂研究进展

CYP1B1酶(Cytochrome P450 1B1,CYP1B1)是细胞色素P450酶(Cytochrome P450 enzyme, CYPs)的一个亚族，能参与多种内、外源性化合物的氧化/还原反应，在多种恶性肿瘤中高表达。CYP1B1酶逐渐成为抗肿瘤药物设计研发的热门靶点，许多学者以CYP1B1酶为靶标蛋白设计的抑制剂，表现出较好的活性和巨大的应用潜力，尤其是在克服肿瘤耐药性中具有重要意义。目前报道的CYP1B1抑制剂种类繁多，活性最佳的化合物是α-萘黄酮(ANF)。主要介绍了较为常见的几类CYP1B1抑制剂，简述了各类化合物的特点以及酶抑制效果，并对CYP1B1抑制剂的发展前景进行了展望。     

联吡啶羧酸铜配合物的合成及其抑制PTP1B活性研究

以一种柔性紫精衍生物1,1′-双(4-羧苄基)-4,4′-联吡啶二氯化物为配体,合成一种新型联吡啶羧酸铜配合物{[Cu(Bpybc)_(1.5)(H_2O)_2]·SO_4}_n,对其结构和组成进行红外光谱、X-射线单晶衍射和元素分析表征。该配合物属于三方晶系,空间群R-3,晶胞参数为:a=17.823 2(14)?,b=17.823 2(14)?,c=26.987(2)?,α=90°,β=90°,γ=120°,V=7 424.3(13)?~3,Z=6,R_(int)=0.134 7,R_1=0.095 0,T=293(2) K。此外,通过体外抑制活性实验研究了该配合物对蛋白酪氨酸磷酸酶1B(PTP1B)的抑制作用,该配合物能够有效抑制PTP1B的活性,其IC_(50)值为0.095μmol/L。     

浅谈水性B1B2与3C1B涂装工艺对比分析

从工艺、设备、成本、管理等多方面对比水性B1B2和3C1B工艺,对工艺的选择给出理论参考.     

糖基化三氮唑水杨酸衍生物的合成及PTP1B抑制活性研究

利用“Click chemistry”将叠氮糖和炔丙基取代水杨醛分子通过Cu催化的1,3偶极环加成反应、氧化和水解三步反应得到一系列糖基化三氮唑水杨醛衍生物,并利用1HNMR、IR、ESI-MS和元素分析对其结构进行表征。通过对目标化合物进行PTP1B 抑制活性测定,结果显示,所有化合物对PTP1B显示出一定的抑制活性, 其中化合物4a活性最佳,IC50为54.52?0.79μM。     

糖基化三氮唑水杨酸衍生物的合成及PTP1B抑制活性

利用"Click chemistry"将叠氮糖和炔丙基取代水杨醛分子通过Cu催化的1,3偶极环加成反应、氧化和水解3步反应得到8个糖基化三氮唑水杨酸衍生物,并利用1HNMR、IR、ESI-MS和元素分析对其结构进行了表征。通过对目标化合物进行PTP1B抑制活性测定,结果显示,所有化合物对PTP1B显示出一定的抑制活性,其中化合物Ⅳa活性最佳,IC50为(54.52±0.79)μmol/L。     

PTP1B抑制剂4,5-二-(2-溴-4,5-二羟基苯甲基)-1,2-二苯酚的合成及生物活性

以藜芦醛(Ⅰ)为起始原料,经过溴代、还原、傅克烷基化、脱甲基4步反应,合成了化合物4,5-二-(2-溴-4,5-二羟基苯甲基)-1,2-二苯酚(Ⅵ),总产率为53.5%。采用1HNMR、13CNMR、HREIMS等进行了结构表征。通过比色法对化合物Ⅵ及中间产物4,5-二-(2-溴-4,5-二甲氧基苯甲基)-1,2-二甲氧基苯(Ⅴ)进行蛋白酪氨酸磷酸酶1B(protein tyrosine phosphatase 1B,PTP1B)抑制活性测定,结果显示化合物质量浓度为20 mg/L时,化合物Ⅴ和Ⅵ的PTP1B酶抑制率分别为25.08%和79.48%,表明化合物Ⅵ具有较好的PTP1B酶抑制活性。     

HPLC法同时测定五维B颗粒中的烟酰胺、维生素B1、维生素B2的含量

目的建立同时测定五维B颗粒中维生素B1、维生素B2、烟酰胺三组分含量的高效液相色谱法.方法采用ODS C18柱、柱长150×4.6mm流动相为甲醇乙腈0.06%己烷磺酸钠和0.04%庚烷磺酸钠的混合液冰醋酸=4530241流速1.2mL/min柱温30℃波长275nm,外标法计算.结果线性范围分别是烟酰胺90～210μg/mL;r=0.999维生素B2 12～32μg/mL;r=0.999、维生素B1 25～65μg/mL;r=0.998,回收率分别为烟酰胺99.5%、维生素B2 99.7%、维生素B1 100.3%.结论本方法分离效果好、辅料无干扰、快速、简便、准确适合于该制剂3组分的同时测定.     

一种水性B1B2紧凑型线体的展车工艺探究

基于环保政策的愈发严格,国内新上马的涂装线基本均采用了水性B1B2工艺,如何在该工艺条件下获得更加饱满的外观表现是每个汽车厂都需要面临的课题.本文基于水性B1B2紧凑型线体进行展车工艺的探究,探索从前处理电泳、胶线、电泳打磨、面漆等一系列过程的控制跟踪要点,进而稳定高效地完成展车级工艺锁定,也可为后续正常商品车的制备在...     

浅析B1B2水性漆工艺规划

以奇瑞商用车河南开封30JPH涂装线为例,介绍了水性漆B1B2工艺喷漆室、色漆闪干、流平段及面漆烘干室体的整体工艺规划及设备布局,对各工艺段的长度、参数、设备应用、材料选择与应用等进行了介绍.     

催化水解法制备单糖和无糖阿维菌素B1

在H2SO4浓度分别为5％(v／v)和10％(v／v)的THF—H2O溶液中对阿维菌素B1(Ⅰ)进行水解，相应得到了单糖AVMB。(Ⅱ)和无糖AVMB1(Ⅲ)；向反应体系中加入0.4％(mol／mo1)的四丁基溴化铵后，(Ⅲ)的收率由原来的50％提高到60．6％；通过改用混合溶剂萃取和增加盐水洗涤步骤，消除了后处理过程中出现的乳化现象，顺利地实现了分离。     

Bioenergetic Status of the Intestinal and Hepatic Cells after Short Term Exposure to Fumonisin B1 and Aflatoxin B1

Fumonisin B1 (FB1) and aflatoxin B1 (AFB1) are frequent contaminants of staple foods such as maize. Oral exposure to these toxins poses health hazards by disrupting cellular signaling. However, little is known regarding the multifaced mitochondrial dysfunction-linked toxicity of FB1 and AFB1. Here, we show that after exposure to FB1 and AFB1, mitochondrial respiration significantly decreased by measuring the oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). The current work shows that the integrity of mitochondria (MMP and ROS), that is the central component of cell apoptosis, is disrupted by FB1 and AFB1 in undifferentiated Caco-2 and HepG2 cells as in vitro models for human intestine and liver, respectively. It hypothesizes that FB1 and AFB1 could disrupt the mitochondrial electron transport chain (ETC) to induce mitochondrial dysfunction and break the balance of transferring H⁺ between the mitochondrial inner membrane and mitochondrial matrix, however, the proton leak is not increasing and, as a result, ATP synthesis is blocked. At the sub-toxic exposure of 1.0 µg/mL for 24 h, i.e., a viability of 95% in Caco-2 and HepG2 cells, the mitochondrial respiration was, however, stimulated. This suggests that the treated cells could reserve energy for mitochondrial respiration with the exposure of FB1 and AFB1, which could be a survival advantage.     

5-O-叔丁基二甲基硅基阿维菌素的合成

以阿维菌素和叔丁基二甲基硅基氯为原料合成 5 O 叔丁基二甲基硅基阿维菌素。其优惠工艺条件为 :反应温度 2 0℃ ,反应时间 2h,阿维菌素∶叔丁基二甲基硅基氯 =1∶3(mol/mol) ,产品收率≥ 90 % ,含量≥ 82 %。     

Functional Characterization of Tomato Phytochrome A and B1B2 Mutants in Response to Heat Stress

Heat stress (HS) is a prevalent negative factor affecting plant growth and development, as it is predominant worldwide and threatens agriculture on a large scale. PHYTOCHROMES (PHYs) are photoreceptors that control plant growth and development, and the stress signaling response partially interferes with their activity. PHYA, B1, and B2 are the most well-known PHY types in tomatoes. Our study aimed to identify the role of tomato ‘Money Maker’ phyA and phyB1B2 mutants in stable and fluctuating high temperatures at different growth stages. In the seed germination and vegetative growth stages, the phy mutants were HS tolerant, while during the flowering stage the phy mutants revealed two opposing roles depending on the HS exposure period. The response of the phy mutants to HS during the fruiting stage showed similarity to WT. The most obvious stage that demonstrated phy mutants’ tolerance was the vegetative growth stage, in which a high degree of membrane stability and enhanced water preservation were achieved by the regulation of stomatal closure. In addition, both mutants upregulated the expression of heat-responsive genes related to heat tolerance. In addition to lower malondialdehyde accumulation, the phyA mutant enhanced proline levels. These results clarified the response of tomato phyA and phyB1B2 mutants to HS.     

多粘菌素B中多粘菌素B1的制备方法研究

用反相制备液相色谱从多粘菌素B中分离得到了高纯度多粘菌素B1单体.采用YMC - ODS -A色谱柱,对制备条件进行了优化.最佳制备条件为:流动相组成,含0.1％三氟乙酸的乙腈/水(21/79,V/V);流速为25 mL/min;单针上样量50 mg;收集波长210 nm;收集信号强度:10 mAU;收集液在40℃下旋...     

维生素B1催化合成N-苯基马来酰亚胺

以苯胺和顺丁烯二酸酐为原料,维生素B1为催化剂,醋酸酐为脱水剂,在丙酮溶剂中采用两步法（醋酐法）合成N-苯基马来酰亚胺。通过对催化剂浓度、反应时间以及脱水剂醋酸酐与顺丁烯二酸酐的配比等工艺条件进行优化,实验结果表明,维生素B1有着很好的催化活性,脱水剂乙酸酐与顺丁烯二酸酐配比为1.6∶1时,催化剂浓度为1.5%（以顺丁烯二酸酐质量计）时,反应时间为4h时为最佳反应条件。在最佳反应条件下,产率可达到63.2%。对丙酮溶剂进行重复使用考察,结果证明溶剂重复使用性好。     

Sphingosine-1-Phosphate Receptor Type 4 (S1P4) Is Differentially Regulated in Peritoneal B1 B Cells upon TLR4 Stimulation and Facilitates the Egress of Peritoneal B1a B Cells and Subsequent Accumulation of Splenic IRA B Cells under Inflammatory Conditions

Background: Gram-negative infections of the peritoneal cavity result in profound modifications of peritoneal B cell populations and induce the migration of peritoneal B cells to distant secondary lymphoid organs. However, mechanisms controlling the egress of peritoneal B cells from the peritoneal cavity and their subsequent trafficking remain incompletely understood. Sphingosine-1-phosphate (S1P)-mediated signaling controls migratory processes in numerous immune cells. The present work investigates the role of S1P-mediated signaling in peritoneal B cell trafficking under inflammatory conditions. Methods: Differential S1P receptor expression after peritoneal B cell activation was assessed semi‑quantitatively using RT-PCR in vitro. The functional implications of differential S1P₁ and S1P₄ expression were assessed by transwell migration in vitro, by adoptive peritoneal B cell transfer in a model of sterile lipopolysaccharide (LPS)‑induced peritonitis and in the polymicrobial colon ascendens stent peritonitis (CASP) model. Results: The two sphingosine-1-phosphate receptors (S1PRs) expressed in peritoneal B cell subsets S1P₁ and S1P₄ are differentially regulated upon stimulation with the TLR4 agonist LPS, but not upon PMA/ionomycin or B cell receptor (BCR) crosslinking. S1P₄ deficiency affects both the trafficking of activated peritoneal B cells to secondary lymphoid organs and the positioning of these cells within the functional compartments of the targeted organ. S1P₄ deficiency in LPS-activated peritoneal B cells results in significantly reduced numbers of splenic innate response activator B cells. Conclusions: The S1P-S1PR system is implicated in the trafficking of LPS-activated peritoneal B cells. Given the protective role of peritoneal B1a B cells in peritoneal sepsis, further experiments to investigate the impact of S1P₄-mediated signaling on the severity and mortality of peritoneal sepsis are warranted.     

Human Protein Tyrosine Phosphatase 1B (PTP1B): From Structure to Clinical Inhibitor Perspectives

Phosphorylation is an essential process in biological events and is considered critical for biological functions. In tissues, protein phosphorylation mainly occurs on tyrosine (Tyr), serine (Ser) and threonine (Thr) residues. The balance between phosphorylation and dephosphorylation is under the control of two super enzyme families, protein kinases (PKs) and protein phosphatases (PPs), respectively. Although there are many selective and effective drugs targeting phosphokinases, developing drugs targeting phosphatases is challenging. PTP1B, one of the most central protein tyrosine phosphatases (PTPs), is a key player in several human diseases and disorders, such as diabetes, obesity, and hematopoietic malignancies, through modulation of different signaling pathways. However, due to high conservation among PTPs, most PTP1B inhibitors lack specificity, raising the need to develop new strategies targeting this enzyme. In this mini-review, we summarize three classes of PTP1B inhibitors with different mechanisms: (1) targeting multiple aryl-phosphorylation sites including the catalytic site of PTP1B; (2) targeting allosteric sites of PTP1B; (3) targeting specific mRNA sequence of PTP1B. All three types of PTP1B inhibitors present good specificity over other PTPs and are promising for the development of efficient small molecules targeting this enzyme.     

紫外分光光度法测定LYCD中维生素B1含量的研究

利用紫外分光光度法测定了LYCD中维生素B1含量,其最佳测试条件为:显色剂用量1.00 mL,显色时间15 min,碱性介质用量1.00 mL,测定波长433 nm.其线性回归方程为y=0.0479x 2.5331,相关系数R2=0.9989,线性范围2.0～10.0 μg·mL-1,平均回收率为100.7%,RSD为1.18%(n=5).该方法简单、易操作、重现性好.