Total synthesis of bis-（2,3-dibromo-4,5-dihydroxyphenyl）-methane as potent PTP1B inhibitor

Protein tyrosine phosphatase 1B （PTP1B） plays an important role as a negative regulator and has been proved to be an effective target for the treatment of type 2 diabetes mellitus. Bis-（2,3-dibromo-4,5-dihydroxyphenyl）-methane 7 was first reported as a natural bromophenol with significant inhibition against PTP1B which was isolated from red algae Rhodomela conrervoides. Intrigued by its astonishing activity （IC50 = 2.4 μmol/L）, compound 7 was synthesized with the overall yield of 24% and evaluated for its PTPIB inhibitory activity compared with natural compound.     

Structural Bases for Hesperetin Derivatives: Inhibition of Protein Tyrosine Phosphatase 1B,Kinetics Mechanism and Molecular Docking Study

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC₅₀ value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC₅₀ = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment.     

Anti—diabetes Agents—I：Tetralone Derivative from Juglans regia

A new compound,4-hydroxy-α-tetralone-4-O-β-D-[6‘‘‘‘‘‘‘‘-O-(3“,4“,5“-trihydroxybenzoyl)glucopyranoside(1),together with a known compound,4-hydroxy-α-tetralone(2),has been isolated from the roots of Juglans regia.2 showed moderate bioactivity against protein tyrosine phosphatase 1B(PTP1B).     

嵌入式Linux设备的高精度IEEE 1588时钟同步实现

IEEE 1588时钟同步协议用于解决分布式网络测控系统中远距离仪器设备之间的同步问题;在分析IEEE 1588时钟同步实现原理的基础上,提出一种嵌入式Linux设备的高精度IEEE 1588时钟同步实现方案;采用专用PHY芯片DP83640在物理层为PTP报文加盖硬件时间戳,设计网络设备驱动与PTP硬件时钟控制驱动,并在用户层利用Linux系统标准API实现IEEE 1588协议软件;实验结果表明,两台设备直接相连时,时钟同步精度可稳定在±100 ns以内。     

含吡啶组块3-脂肪基-1, 2, 4-三唑并[3,4-b]-1,3,4噻二唑衍生物的合成及生物活性

分别将6种脂肪酸与二氨基硫脲反应,合成了6种含不同碳数的3-脂肪基-1,2,4-三唑(1a~1f),其中化合物1e和1f为首次合成。在三氯氧磷存在下,分别将化合物1a~1f与4-吡啶甲酸和2,6-吡啶二甲酸反应,首次高产率合成了12种三唑并噻二唑衍生物(2a~2f)和(3a~3f)。为对比引入3-脂肪基和吡啶组块对生物活性的影响,分别合成了3-苯基含吡啶组块产物(5)、双枝3-苯基含吡啶组块化合物(6)、不含吡啶组块的化合物(7a~7c)和(8a~8c)。应用IR、1H NMR和HRMS等技术手段对19种新物质进行了结构表征,并研究了其对Cdc25B和PTP1B的抑制性能,研究结果表明,含有吡啶组块的双枝脂肪基化合物3b、3d、3e和3f对Cdc25B有良好的抑制活性,IC50值(mg/L)分别为1.12±0.27、2.72±1.07、0.72±0.05和4.97±0.93;化合物2b、3d和5对PTP1B表现出较高的抑制活性,IC50值(mg/L)分别为0.98±0.13、1.33±0.11和2.18±0.20。     

Studies on phase transition processes of radiation synthesized hydrogels

PAM hydrogel and P(AM-NaA) (polyacrylamide-sodium acrylate) copolymer hydrogels with different AM/NaA ratios by radiation polymerization of aqueous solutions were synthesized. For further developing sensitive materials, we investigated the phase transition processes of all of the hydrogels in acetone-water solutions (so called A-W).     

环状多聚二硫醚化合物的合成及初步生物活性研究

通过二硫醇化合物氧化的方法合成了8个具有环状结构的多聚二硫醚化合物. 得到的化合物经IR, ¹H NMR, ¹³C NMR和HREIMS确证其结构, 部分化合物还经晶体X衍射方法验证. 通过对II型糖尿病靶标蛋白酪氨酸磷酸酯酶(PTP1B)抑制活性的分析, 发现一些化合物具有一定的PTP1B抑制活性.     

Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy

Protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) play non-redundant negative regulatory roles in T-cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU-14 for both PTP1B and TC-PTP. DU-14 mediated PTP1B and TC-PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination- and proteasome-dependent. DU-14 enhances IFN-γ induced JAK1/2-STAT1 pathway activation and promotes MHC-I expression in tumor cells. DU-14 also activates CD8⁺ T-cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU-14 induces PTP1B and TC-PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU-14, as the first PTP1B and TC-PTP dual degrader, merits further development for treating cancer and other indications.     

5-Alkylpyrrole-2-carboxaldehyde derivatives from the Chinese sponge Mycale lissochela and their PTP1B inhibitory activities

Two new 5-alkylpyrrole-2-carboxaldehyde derivatives,mycalenitrile-15(1) and mycalenitrile-16(2),along with five known related ones(3-7),were isolated from the South China Sea sponge Mycale lissochela.The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis and by comparison of their NMR data with those reported in the literature.In bioassay,compounds 1 and 7 exhibited significant PTPIB(Protein-tyrosine phosphatase 1B,a recognized target for diabetes and obesity) inhibitory activities with IC_(50) values of 8.6 and 3.1 μmoI/L,respectively.A preliminary SAR analysis of the isolated compounds with their PTP1 B inhibitory effects was described.     

基于咔唑的新型碳酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性评价

合成出了一系列新型基于咔唑的单-/双-碳酰腙衍生物3和4.利用1H NMR、13C NMR、IR和元素分析对其进行了结构表征.评价了目标化合物对蛋白酪氨酸磷酸酶1B(PTP1B)的抑制活性,讨论了结构与活性的关系.实验结果显示,大部分化合物对PTP1B具有良好的抑制活性,其中1,5-双[(9-丁基-3-咔唑基)亚甲基]碳酰腙(4c)的抑制活性最高,IC50=(4.81±0.41)mmol/L,且活性高于对照药物齐墩果酸.对目标化合物1-[(9-庚基-3-咔唑基)亚甲基]碳酰腙(3f)和4c进行分子对接研究和密度泛函理论(DFT)计算.分子对接结果表明,化合物3f和4c结合到PTP1B酶由螺旋α3和α6形成的活性位点,与PTP1B酶通过氢键、极性、疏水和p-p等相互作用形成了稳定的复合物.