1′-Acetoxychavicol Acetate as an Inhibitor of Phagocytosis of Macrophages

We screened extracts of edible plants for inhibitors of phagocytosis by peritoneal exudate macrophages. 1’-Acetoxychavicol acetate was isolated from the ethyl acetate extract of Languas galanga, and this compound strongly inhibited phagocytosis at an IC₅₀ value of 1.2 μM with negligible effects on pinocytosis and cell viability. Target(s) of 1′-acetoxychavicol acetate was suggested to be downstream of the signal transduction pathway that is mediated by protein kinase C.     

1′-Acetoxychavicol Acetate Isolated from Alpinia galanga Ameliorates Ovalbumin-Induced Asthma in Mice

The World Health Organization reports that 235 million people are currently affected by asthma. This disease is associated with an imbalance of Th1 and Th2 cells, which results in the upregulation of cytokines that promote chronic inflammation of the respiratory system. The inflammatory response causes airway obstruction and can ultimately result in death. In this study we evaluated the effect of 1′-acetoxychavicol acetate (ACA) isolated from Alpinia galanga rhizomes in a mouse model of ovalbumin (OVA)-induced asthma. To generate the mouse model, BALB/c mice were sensitized by intraperitoneal injection of OVA and then challenged with OVA inhalation for 5 days. Mice in the vehicle control group were sensitized with OVA but not challenged with OVA. Treatment groups received dexamethasone, 25 mg/kg/day ACA, or 50 mg/kg/day ACA for 5 days. Asthma-related inflammation was assessed by bronchoalveolar lavage fluid cell counts and histopathological and immunohistochemical analysis of lung tissues. Our results showed that ACA reduced the infiltration of white blood cells (especially eosinophils) and the level of IgE in the lungs of mice challenged with OVA and suppressed histopathological changes such as airway remodeling, goblet-cell hyperplasia, eosinophil infiltration, and glycoprotein secretion. In addition, ACA inhibited expression of the Th2 cytokines interleukin (IL)-4 and IL-13, and Th1 cytokines IL-12α and interferon-γ. Because asthmatic reactions are mediated by diverse immune and inflammatory pathways, ACA shows promise as an antiasthmatic drug candidate.     

1′-Acetoxychavicol acetate-induced cytotoxicity is accompanied by a rapid and drastic modulation of glutathione metabolism

The effect of 1′-acetoxychavicol acetate (ACA), an anticarcinogenic compound naturally obtained from rhizomes and seeds of South East Asia plants, on the intracellular concentration of glutathione and the activities of enzymes related to glutathione metabolism was studied in Ehrlich ascites tumor cells. We showed in a previous study that ACA induced apoptosis in tumor cells and the cell death was reversed by the addition of N-acetlycysteine or glutathione ethylester. Here we found that ACA caused a rapid decrease in glutathione level in less than 10 min after ACA exposure. At the time, glutathione reductase activity was significantly inhibited and gamma-glutamyl cysteine increased by ACA exposure. These results show that ACA caused the decrease in the intracellular GSH levels in Ehrlich ascites tumor cells, suggesting that ACA-induced decrease of the cellular GSH levels can lead to growth arrest of cancer and enhancement of the efficacy other anticancer drugs.     

Virus-Infection or 5′ppp-RNA Activates Antiviral Signal through Redistribution of IPS-1 Mediated by MFN1

In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-β promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5′ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.     

嘧啶二酮类TRPA1抑制剂研究进展

TRPA1是一种新的瞬时受体电位离子通道,与疼痛、神经病变等有关。本文着眼于TRPA1抑制剂的主要专利申请,概述近年来嘧啶二酮类TRPA1抑制剂的研究进展。     

Syntheses and antitumor activities of N′1,N′3-dialkyl-N′1,N′3-di-(alkylcarbonothioyl) malonohydrazide: The discovery of elesclomol

A series of N′¹,N′³-dialkyl-N′¹,N′³-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure–activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.     

TRPA1传导皮肤角质细胞温热信息的机制研究

目的 探究角质细胞中的温热信息是如何被传导至下游背根神经节（DRG）中的TRPA1离子通道。方法 采用单细胞钙离子成像技术,利用TRPA1过表达系统以及野生型和TRPA1基因敲除小鼠,联合TRPA1激动剂（BITC）和抑制剂（HC-030031）检测H₂O₂在DRG神经元温热感知中的作用及其与TRPA1的相关性。在不同温热条件下培养皮肤角质细胞,并提取角质细胞RNA;采用RNA-seq分析比较不同温度培养的角质细胞基因表达异同,筛选皮肤角质细胞传导温热信息的候选因子。结果 过表达TRPA1以及DRG神经元中的TRPA1均可在H₂O₂存在情况下被温热激活,而温热范围内不同温度可影响皮肤角质细胞中与H₂O₂产生有关的趋化因子配体2（CCL2）和核心蛋白聚糖（DCN）基因的表达。结论 H₂O₂相关因子可能参与TRPA1介导的温热传导过程。     

Enhanced Cofactor and Allosteric Effector Activity of 3′-Pyrophospho Coenzyme A and Its Acetate

To prepare a chemically modified urokinase that does not dissociate into two peptide fragments upon reduction of its disulfide bridge, we cross-linked the enzyme intramolecularly with various bifunctional imidoesters. The enzyme underwent the intramolecular cross-linking most moderately by the reaction at 4^QC for 5 hr with 3mm dimethyl suberimidate in 0.1 M potassium phosphate buffer (pH 9.0). The cross-linked urokinase isolated by gel filtration with a yield of 25 % showed a specific activity of 76,000 International Units/mg protein, which corresponds to 53% of that of the native enzyme. Although the modified enzyme was similar to the native urokinase in some properties such as the autocatalytic self-digestion and the low affinity to fibrin, it showed higher in vivo and in vitro stabilities than the native one.     

2′-Deoxy-1-methylpseudocytidine,a stable analog of 2′-deoxy-5-methylisocytidine

2′-Deoxy-5-methylisocytidine is widely used in assays to personalize the care of patients infected with HIV, hepatitis C, and other infectious agents. However, oligonucleotides that incorporate 2′-deoxy-5-methylisocytidine are expensive, because of its intrinsic chemical instability. We report here a C-glycoside analog that is more stable and, in oligonucleotides, pairs with 2′-deoxyisoguanosine, contributing to duplex stability about as much as a standard 2′-deoxycytidine and 2′-deoxyguanosine pair.     

Synthesis of the 2′-,3′-Didehydro-2′-,3′-dideoxy and 2′-,3′-Dideoxy Derivatives of 6-Azauridine and a New Route to 2′-,3′-Didehydro-2′-,3′-dideoxy-5-chlorouridine

Abstract

The 5′-O-(4,4′-dimethoxytrityl) and 5′-O-(tert-butyldimethylsilyl) derivatives of 2′-,3′-O-thiocarbonyl-6-azauridine and 2′,3′-O-thiocarbonyl-5-chlorouridine were synthesized from the parent nucleosides by reaction with 4, 4′-dimethoxytrityl chloride and tert-butyldimethylsilyl chloride, respectively, followed by treatment with 1,1′-thiocarbonyldiimidazole. Introduction of a 2′-,3′-double bond into the sugar ring by reaction of the 5′-protected 2′-,3′-O-thionocarbonates with 1, 3-dimethyl-2-phenyl-1, 3, 2-diazaphospholidiine was unsuccessful, but could be accomplished satisfactorily with trimethyl phosphite. Reactions were generally more successful with the 5′-silylated than with the 5′-tritylated nucleosides. Formation of 2′-,3′-O-thiocarbonyl derivatives proceeded in higher yield with 5′-protected 6-azauridines than with the corresponding 5-chlorouridines because of the propensity of the latter to form 2,2′-anhydro derivatives. In the reaction of 5′-O-(tert-butyldimethylsilyl)-2′-,3′-O-thiocarbonyl-6-azauridine with trimethyl phosphite, introduction of the double bond was accompanied by N³-methylation. However this side reaction was not a problem with 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-O-thioarbonyl-5-chlorouridine. Treatment of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-6-azauridine with tetrabutylammonium fluoride followed by hydrogenation afforded 2′-,3′-dideoxy-6-azauridine. Deprotection of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-5-chlorouridine yielded 2′-,3′-didehydro-2′-,3′-dide-oxy-5-chlorouridine.     

C1′ Acylated Derivatives of 2′-Deoxyuridine. Photolabile Precursors of 2′-Deoxyuridin-1′-yl

Abstract

ABSTRACT

C1′ acylated derivatives of 2′-dcoxyuiidinc (1a-c) were synthesised from 1-[3-deoxy-β-D-psieofiiraiiosylliii.acil (6). The acyl group is introduced via the C1′ aldehyde (11). Following nucleophilic addition, the ketones (1a-c) are obtained via periodinane oxidation and desilylation with NH₄F.     

Isolation,structure determination and biological activity of A-16686 factors A′ 1, A′ 2 and A′ 3 glycolipodepsipeptide antibiotics

Summary WhenActinoplanes strain ATCC 33076, the producer of A-16686 A1, A2 and A3 complex, is fermented in a suitable medium three additional factors, designated A1, A2 and A3 are produced. These were isolated and characterized, and were shown to differ from the parent components of the original complex by lacking one mannose unit. Bioconversion of A factors into A factors was achieved by incubation with the mycelium ofActinoplanes ATCC 33076. Factor A2 has better antibacterial activity than A2 against some bacteria.     

靶向TRPA1通道的药物开发研究进展

瞬时受体势(Transient Receptor Potential,TRP)通道是一种非选择性阳离子通道,广泛分布于神经和非神经细胞中。TRPA1作为TRP通道的一个亚型,是一种温度敏感型的TRP通道,其温度激活阈值与物种有关。在小鼠体内,TRPA1可以被低温(17℃)激活,然而在绿安乐蜥体内TRPA1的温度激活阈值却达到了35.8℃。TRPA1除了可以响应温度刺激之外,还可以被化学刺激、机械刺激等多种理化方式激活。TRPA1基因的功能获得性突变会导致家族性发作性疼痛综合征。由于TRPA1在温度感知、痛觉产生、哮喘、瘙痒等众多生理与病理过程中发挥着重要作用,因而TRPA1受到了广泛关注。文章总结TRPA1通道的生理特性,并对其参与的机体生理调节及靶向TRPA1通道的药物开发现状和前景进行综述,以期为临床上治疗相关疾病提供理论基础。     

TRPA1 Agonists—Allyl Isothiocyanate and Cinnamaldehyde—Induce Adrenaline Secretion

Thermosensitive transient receptor potential (TRP) channels, especially TRPV1 and TRPA1, are activated by the pungent compounds present in spices. TRPV1 activation by the intake of capsaicin, the irritant in hot pepper, induces adrenaline secretion and increases energy consumption. TRPV1 is mainly expressed in the sensory neurons and coexpressed with TRPA1 at a high frequency. However, the mechanism underlying adrenaline secretion by TRPA1 agonists such as allyl isothiocyanate (AITC) and cinnamaldehyde (CNA), the pungent ingredients in mustard and cinnamon, is not known. We examined whether AITC and CNA could induce adrenaline secretion in anesthetized rats. An intravenous injection of AITC or CNA (10 mg/kg) increased adrenaline secretion. These responses disappeared completely in capsaicin-treated rats with an impaired sensory nerve function. Moreover, pretreatment with cholinergic blockers (hexamethonium and atropine) attenuated the AITC- or CNA-induced adrenaline secretion. These results suggest that TRPA1 agonists activate the sensory nerves and induce adrenaline secretion via the central nervous system.     

Design,synthesis, X-ray studies,and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1′-P2′ ligands

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1′-P2′ tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K_i = 13.2 nM, IC₅₀ = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (K_i = 62 pM and 14 pM, respectively) and antiviral activity (IC₅₀ = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.     

A Regioselective,Chemoenzymatic Synthesis of Sucrose- 1′-Methacrylate

Pure sucrose is inexpensive and readily available, making this disaccharide a highly desirable starting material for new polymers. In order to achieve a clean polymerization, the disaccharide must be regioselectively monofunctionalized in good yield. This paper describes the practical, enzyme-mediated synthesis of sucrose-1 ′-methacrylate 2 from sucrose and vinyl methacrylate using subtilisin Carlsberg (Sigma, Protease VIII), a readily available bacterial serine protease. A key aspect of this process, ascertaining the positional selectivity of acylation, was unambiguously accomplished using ¹H-detected (¹H, ¹³C) one-bond shift correlation (HMQC) spectroscopy and¹H-detected (¹H, ¹³C) multiple bond correlation (HMBC) spectroscopy.     

Facile synthesis of 2′,5′-dideoxy-, 2′,3′-dideoxy- and 3′-deoxy-1,N 6-ethenoadenosine nucleosides

Facile synthetic methods of 2′,5′-dideoxy-, 2′,3′-dideoxy- and 3′-deoxy-1,N ⁶-ethenoadenosine nucleosides by either an enzymatic dideoxyribosyl transfer reaction or a simple chemical reaction were proposed. The synthetic products were isolated and purified by preparative HPLC and their structures were confirmed by¹H NMR (500 MHz) and FAB-MS including high resolution mass measurement. These modified nucleoside analogs have not been reported yet. Therefore, these modified nucleoside analogs are of potential value to be studied further for biological activity such as anticancer or antiviral.