An efficient and enantioselective aerobic oxidation of 4-substituted pyrazolones has been developed by phase transfer catalysis. Using visible light as the driving force and O2 (in air) as the oxidant, broad scopes (38 examples) of pyrazolones bearing an oxygen-attached carbon stereocenter at C-4 position were obtained in high yields (up to 98%) and excellent enantioselectivities (up to 93% ee) under mid conditions. The ready availability of catalyst, ease of operation, and low-cost and eco-friendly nature highlighted the practical utility of this visible light-promoted enantioselective aerobic oxidation.

A novel tumor-targeted glutathione responsive Glycosylated-Camptothecin nanosupramolecular prodrug (CPT-GL NSp) was designed and fabricated via a disulfide bond. The effects of glycoligand with different polarities on solubility, self-assembly, stability, cellular uptake, and glutathione responsive cleaving were explored, and an optimal glycosylated ligand was selected for nanosupramolecular prodrug. It has been found that CPT-GL NSp exhibited higher drug loading than traditional nanoparticles. Among of which maltose modified NSp had the strongest anti-tumor effects than that of glucose and maltotriose. CPT-SS-Maltose had a similar anti-tumor ability to Irinotecan (IR), but the superior performance in solubility, hemolysis, and uptake of HepG2 cells.

Ligands are an important part of targeted drug delivery systems. Optimised lignads not only improve the target efficiency, but also enhance therapeutical effect of drugs. In our research, five sugar molecules (Mannose, Galactose, Glucose, Malt disaccharide, and Maltotriose) conjugated PEG600-DSPE were synthesised, of which polysaccharides were first discovered by us as sugar ligands to modify liposomes, which interacts with over expressive GLUT on cancer cells. DiO was encapsulated as fluorescent probe to evaluate their cellular uptake abilities of targeting C6 glioma cells, and the distribution in different visceral organs of rats. The results demonstrated that Malt disaccharide and Glucose-PEG600-DSPE had the strong efficiency of cellular uptake by C6 glioma cells. The distribution and accumulation of liposomes showed that different sugars modified liposomes could target different visceral organs in rats. It has provided a novel idea for ligand selectivity and optimisation of nanocarriers for tumour targeted therapy.

Acute and persistent myocardial ischemia is the main cause of acute myocardial infarction (AMI) and heart failure. MicroRNA-21(miR-21) contributes to the pathophysiological consequences of acute myocardial infarction by targeting downstream crucial regulators. Thus, miR-21 mimics are a promising strategy for the treatment of AMI. However, their poor stability and insufficient cellular uptake are the major challenges. Herein, we encapsulated miR-21 mimics into liposomes modified with the cardiac troponin T (cTnT) antibody for targeted delivery of miR-21(cT-21-LIPs) to the ischemic myocardium. The cT-21-LIPs exhibited enhanced targeting efficiency to hypoxia primary cardiomyocytes in vitro and improved accumulation in the ischemic heart of AMI rats after injection via the tail vein due to the specifical target to overexpressed troponin. The cT-21-LIPs could significantly improve the cardiac function and decrease the infarct size after AMI, while maintaining the viability of cardiomyocytes. This design provides a novel strategy for delivering small nucleotide drugs specifically to the infarcted heart, which may find great potential in clinics.

聚乙二醇(PEG)是一种惰性、非致癌性聚合物,目前是修饰生物活性分子和纳米粒子表面的首选聚合物之一[1-2].聚乙二醇已被证明可以增强疏水性药物、蛋白质、核酸、脂质体的溶解性、提高稳定性和延长循环时间[3-4].此外,PEG 还能通过增强渗透和保留(EPR)效应实现特异性肿瘤靶向治疗[5-6].PEG 现已成为生物技术和生物医学界关注的焦点,广泛应用于大分子与表面的连接、药物和脂质体的靶向性、纳米颗粒功能化等诸多领域[7-11].

Zedoary turmeric oil (ZTO) has a strong antitumor activity. However, its volatility, insolubility, low bioavailability, and difficulty of medication owing to oily liquid limit its clinical applications. Sol id lipid nanoparticles can provide hydrophobic environment to dissolve hydrophobic drug and solidify the oily active composition to decrease the volatility and facilitate the medication. Chitosan has been widely used in pharmaceutics in recent years and coating with chitosan further enhances the internalization of particles by cells due to charge attract. Here, Chitosan (CS)-coated solid lipid nanoparticles (SLN) loaded with ZTO was prepared and characterized using dynamic laser scanner (DLS) and transmission electron microscope (TEM). The uptake and distribution of drug were evaluated in vitro and in vivo. The average sizes of ZTO-SLN and CS-ZTO-SLN were 134.3 +/- 3.42 nm and 210.7 +/- 4.59 nm, respectively. CS coating inverted the surface charge of particles from -8.93 +/- 1.92 mV to +9.12 +/- 2.03 mV. The liver accumulation of CS-ZTO-SLN was higher than ZTO-SLN (chitosan-uncoated particles) by analysis of tissue homogenate using HPLC, and the bioavailability of ZTO was also obviously improved. The results suggested that SLN coated with CS improved the features of ZTO formulation and efficiently deliver drug to the liver. (C) 2020 Published by Elsevier B.V.

Previous studies have shown that curcumin (Cur) induced by ultrasound has protective effects on atherosclerosis even if low bioavailability of the Cur. The enhancement of bioavailability of the Cur further improved the curative effect of sonodynamic therapy (SDT) on atherosclerosis through nanotechnology. Nanosuspensions as a good drug delivery system had obvious advantages in increasing the solubility and improving the effectiveness of insoluble drugs. The aim of this study was to develop curcumin nanosuspensions (Cur-ns) which used polyvinylpyrrolidone (PVPK30) and sodium dodecyl sulfate (SDS) as stabilizers to improve poor water solubility and bioavailability of the Cur. And then the therapeutic effects of Cur-ns-SDT on atherosclerotic plaques and its possible mechanisms would be investigated and elucidated. Cur-ns with a small particle size has been successfully prepared and the data have confirmed that Cur-ns could be more easily engulfed into RAW264.7 cells than free Cur and accumulated more under the stimulation of the ultrasound. Reactive oxygen species (ROS) inside RAW264.7 cells after SDT led to the decrease of mitochondrial membrane potential (MMP) and the higher expression of cleaved caspase-9/3. The results of in vivo experiments showed that Cur-ns-SDT reduced the level of total cholesterol (TC) and low density lipoprotein (LDL) and promoted the transformation from M1 to M2 macrophages, relieved atherosclerosis syndrome. Therefore, Cur-ns-SDT was a potential treatment of anti-atherosclerosis by enhancing macrophages apoptosis through mitochondrial pathway and inhibiting the progression of plaques by interfering with macrophages polarization.

化学药物治疗简称化疗,是癌症治疗的有效手段之一,阿霉素(doxorubicin,DOX)、紫杉醇(paclitaxel,PTX)等用于化疗的细胞毒性物质可显著改善癌症患者的生活质量[1].但多数成药的细胞毒性成分对肿瘤细胞选择性差,且存在非靶向性的全身副作用.迄今为止,这些问题仍然是化学治疗的主要瓶颈[2].为了提高肿瘤细胞选择性,改善抗癌疗效,多功能纳米系统研发受到了普遍关注[3].常见的药物递送系统包括:胶束[4]、脂质体[5]、金属纳米粒子[6]、二氧化硅粒子等[7].

以聚乙二醇1500为起始原料,经两步官能团转化得到双叠氮基聚乙二醇(N3-PEG1500-N3),该中间体经有机相还原、水相终止,实现双叠氮基的单侧还原.反应选择性及转化率经液质联用(组分中代表性准分子离子峰的液相积分面积比例)进行评价.利用单因素实验,确定氨基叠氮聚乙二醇(NH2-PEG1500-N3)最佳液液两相反应条件如下:N3-PEG1500-N3与三苯基膦的物质的量比为1.0:1.1,有机相为V(甲苯):V(二氯甲烷)=3:2的混合溶液,水相为2.0 mol/L盐酸溶液,两相体积比1:1,35℃下反应12 h,经柱分离提纯得NH2-PEG-N3,收率72％,单侧叠氮基还原选择性达97％.实验结果表明,该法制备NH2-PEG1500-N3具有纯度高、方法简便等特点.产物经1HNMR、13CNMR、IR和HRMS进行结构确证.利用NH2-PEG-N3实现了叠氮封端功能化磷脂的合成.

A mild, reagent-cyanide-free, and efficient synthesis of O-phosphinoyl-protected cyanohydrins from readily available α-substituted malononitriles was realized using diarylphosphine oxides in the presence of O2. Mechanistic studies indicated that in addition to the initial aerobic oxidation of the malononitrile derivative notable features of this process include the formation of a tetrahedral intermediate and a subsequent intramolecular rearrangement. The phosphinoyl-protecting group can be removed by alcoholysis or by reduction with DIBAL-H.

A facile and efficient asymmetric α-alkylation of β-keto esters and β-keto amides has been achieved by phase-transfer catalysis.

It has been reported that p-aminophenyl-alpha-D-mannopyranoside modified liposomes (MAN-LIP) had specific affinity with glucose transporter 1 (GLUT1), which could facilitate the entry of carriers into healthy mice brain. Here, we report the use of MAN-LIP to targeting delivery to transient ischemic mice brain and discuss the dynamic relationship between the accumulation of MAN-LIP in ischemic regions and GLUT1 involved in the transport process. In vitro, oxygen glucose deprived/reoxygenation (OGD/R), simulating cerebral transient ischemia, dynamically up-regulated GLUT1 expression in C6 glioma cells and enhanced its internalized capacity, which influenced the transport of MAN-LIP. In this mechanism, OGD/R led to a linear decrease of MAN-LIP transport across the blood brain barrier (BBB) by bEND. 3 cells in vitro (2.1 fold, 1.8 fold and 1.4 fold at OGD/R 4 h, 12 h, and 24 h, compared with normal condition, respectively) and result to a converse-V shape increase of MAN-LIP transport by C6 glioma cells (1.5 fold, 2.1 fold and 1.8 fold compared with normal at OGD/R 4 h, 12 h and 24 h, respectively). In vivo time-dependent optical imaging showed that MAN-LIP could have a higher accumulation (linear enhancement) in ischemia/reperfusion region (I/R) compared with LIP, which was consistent with the dynamic expression of GLUT1 ex vivo. Overall, the changed role of GLUT1 in the various tissues could have impact on the entry of MAN-LIP into the brain and its accumulation in the affected regions, which should be taken into account when we designed drug delivery system targeting to cerebral ischemic stroke.

An efficient and enantioselective photo-organocatalytic alpha-hydroxylation of beta-dicarbonyl compounds using molecular oxygen was extended. This simple catalytic procedure is applicable to a range of beta-keto esters and beta-keto amides (30 examples) with a new series of C-2'-substituted phase transfer catalysts in good enantiopurity (up to 90% ee) and yield (up to 99%). Moreover, the reaction was successfully scaled up to gram quantity without any loss of enantioselectivity.

The chiralα-hydroxy-β-dicarbonyl is a common structural motif in a variety of natural products and pharmaceuticals and the most convenient way to obtain chiral α-hydroxylation compounds is the direct asymmetric oxidation of 1,3-dicarbonyl compounds.Thus,research on enantioselectiveα-hydroxylation ofβ-keto esters possess great value.This paper makes a brief summary of cinchona alkaloid derivatives,diterpenoid alkaloid derivatives,S-timolol analogues and phase-transfer catalysts applied to direct enantioselective hydroxylation of β-keto ester compounds.The possible mechanism of these catalysts is believed to be the outcome of combined action of various intermolecular forces, namely hydrogen bonding,π-π stacking and electrovalent bonding.

Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1.

Scheme 1. Diterpenoid alkaloid lappaconine and preparation of lappaconine derivatives.[a] State Key Laboratory of Fine ChemicalsSchool of Pharmaceutical Science and TechnologyDalian University of TechnologyNo. 2 Linggong Road, Ganjingzi District, Dalian, LiaoningProvince 116012, P. R. ChinaE-mail: mengqw@dlut.edu.cnhttp://ceb.dlut.edu.cn/index.html[b] Department of Pharmaceutics, Daqing CampusHarbin Medical UniversityNo. 1 Xinyang Road, Gaoxin District, Daqing, HeilongjiangProvince 163319, P. R. ChinaSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201402019.

We have established that 15-hydroxyeicosatetraenoic acid is an important factor in regulation of pulmonary vascular remodeling (PVR) associated with hypoxia-induced pulmonary hypertension (PH), which is further metabolized by 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to form 15-ketoeicosatetraenoic acid (15-KETE). However, the role of 15-PGDH and 15-KETE on PH has not been identified. The purpose of this study was to investigate whether 15-PGDH/15-KETE pathway regulates hypoxia-induced PVR in PH and to characterize the underlying mechanisms. To accomplish this, Immunohistochemistry, Ultra Performance Liquid Chromatography, Western blot, bromodeoxyuridine incorporation and cell cycle analysis were preformed. Our results showed that the levels of 15-PGDH expression and endogenous 15-KETE were drastically elevated in the lungs of humans with PH and hypoxic PH rats. Hypoxia stimulated pulmonary arterial smooth muscle cell (PASMC) proliferation, which seemed to be due to the increased 15-PGDH/15-KETE. 15-PGDH/15-KETE pathway was also capable of stimulating the cell cycle progression and promoting the cell cycle-related protein expression. Furthermore, 15-KETE-promoted cell cycle progression and proliferation in PASMCs depended on protease-activated receptor 2 (PAR-2). ERK1/2 signaling was likely required for 15-PGDH/15-KETE-induced PAR-2 expression under hypoxia. Our study indicates that 15-PGDH/15-KETE stimulates the cell cycle progression and proliferation of PASMCs involving ERK1/2-mediated PAR-2 expression, and contributes to hypoxia-induced PVR.

The reaction proceeds under mild conditions with good enantioselectivities and affords the corresponding hydroxylation products in good yields.

Cinchona alkaloid-derived chiral quaternary ammonium organocatalysts were developed. The catalyst with a bulky 1-adamantoyl group at the C-9 position promoted the enantioselective α-hydroxylation of β-oxo esters and resulted in the corresponding products in 35-95% yields and 58-90% ee. The reaction was successfully scaled to a gram-quantity scale with a similar yield without loss of enantioselectivity.