抗肿瘤一氧化氮供体药物研究进展

一氧化氪（NO）是重要的信使物质和效应分子，参与了体内多种生理和病理过程。研究表明，NO具有多种机制的抗肿瘤作用。一些NO供体药物已被证明具有良好的抗癌活性，显示出其应用潜力和价值。通过控制NO在适当的部位释放并杀死肿瘤细胞，实现药物的靶向性，是NO供体类药物治疗癌症的一个新领域和重要的发展方向。现综述抗肿瘤NO供体、一氧化氮供体型非甾体抗炎药（NO-NSAIDs）、靶向NO供体药物的研究新进展。     

硝酸酯类一氧化氮供体药物研究进展

一氧化氮（nitric oxide, NO）具有多种生理活性,为了使经典药物发挥更广泛或者更好的治疗作用,研究人员将能释放NO的硝酸酯类基团与这些药物骈合,得到了一系新型硝酸酯类供体药物。这些药物涉及解热镇痛药、非甾体抗炎药、循环系统药和化学治疗药等。这类药物在体内被分解为母体药物和NO,二者分别发挥生理效应,达到协同增效作用。过去几年里,新型硝酸酯类NO供体药物受到了广泛研究,并取得了一些成果。文中综述了这类药物近年来的研究进展。     

靶向作用的一氧化氮供体及其相关药物

一氧化氮（NO）是一种自由基气体分子，早在1972年就由Joseph Priestley发现，但一直到20世纪80年代它在体内的生物学特性才得到确认。     

萘普西诺的合成

萘普生与由四氢呋喃经HCl开环得到的4-氯-1-丁醇成酯,得到(S)-2-(6-甲氧基-2-萘基)丙酸-4-氯丁酯,最后经硝酸银硝化制得非甾体抗炎药萘普西诺,总收率约83%(以萘普生计).     

一氧化氮供体药物的研究进展与应用前景

一氧化氮（NO）供体药物具有抗增生，抗血小板聚集，参与免疫调节等作用。并在缺血再灌注损伤中扮重要角色。NO供体药物在心血管疾病，阳痿和妊高征的治疗中占重要地位，并可望成为急性胰腺炎和白血病的治疗药物之一。     

呋咱氮氧化物类一氧化氮供体型药物的研究进展

一氧化氮作为生物信使或效应分子在体内发挥重要的生理作用,且其体内水平异常与多种疾病的发生和发展密切相关。因此,一氧化氮供体型药物的研究备受关注。呋咱氮氧化合物即是一类重要的一氧化氮供体,其与某些药物分子偶联而合成的一氧化氮供体型药物可提高药物的药理活性。综述具不同药理作用的呋咱氮氧化物类一氧化氮供体型药物的研究进展。     

一氧化氮阿司匹林(NCX-4016)体外抗氧化作用

目的：探讨一氧化氮阿司匹林（NCX-4016）的体外抗氧化低密度脂蛋白的效应.方法：健康成人空腹12 h新鲜混合静脉血,离心取血浆.采用密度梯度超速离心法分离低密度脂蛋白（LDL）,鉴定其纯度并检测其浓度.以Cu^2＋体外诱导LDL氧化,制备LDL体外氧化模型,采用紫外分光光度计于234nm监测LDL氧化过程中共轭二烯键（CD）的形成情况.将NCX-4016加入反应体系,观察药物对反应体系内形成动力曲线的影响以及对LDL氧化的作用,同时以硫代巴比妥酸反应活性物（TBRAS）测定诱导LDL氧化前后过氧化脂质生成量的影响.结果：NCX-4016能够降低CD的最大生成量、延长潜伏期,降低LDL氧化产物丙二醛（MDA）的含量,并具有浓度依赖效应关系（P＜0.05）.在相同浓度条件下NCX-4016的抗LDL氧化效应显著高于阿司匹林（P＜0.05）.结论：NCX-4016对Cu^2＋诱导的LDL的氧化具有明显抑制作用.     

一氧化氮及其供体的临床试验和医用前景

一氧化氮及其供体的临床试验和医用前景贾力１裴仁九刘锡钧（福州东方医院临床药理基地，福州３５００２５）中国图书分类号Ｒ９１４．３；Ｒ９７２Ｆｕｒｃｈｇｏｔ在８０年代初期开创的血管内皮细胞释放松弛因子（Ｅｎｄｏｔｈｅｌｉｕｍ－ｄｅｒｉｖｅｄｒｅｌａｘｉｎ...     

一氧化氮供体与心血管病治疗药

目的介绍一氧化氮供体药物的研究进展。方法根据相关文献 ,进行分析整理和归纳。结果与结论为一氧化氮供体药物的研究和开发提供了参考     

一氧化氮供体/一氧化氮供体型化合物在肿瘤治疗中的研究进展

一氧化氮(NO)是生物体中重要的信号分子,对肿瘤生长具有双重作用。低浓度NO通过参与血管形成等效应促进肿瘤生长,而高浓度则通过诱导细胞凋亡等机制抑制肿瘤细胞增殖[1]。除诱导型一氧化氮合酶(iNOS)经刺激因素(细胞因子等)作用能产生大量NO外,NO供体也是获得高浓度NO的有效途径。NO供体能在生理状态下释放游离NO或NO类似物,有效补充体内NO不足以及恢复NO正常的信号传导。NO供体具有多种结构类型,如硝酸和亚硝酸的有机酸酯、亚硝基硫醇、呋咱氮氧化合物和偶氮鎓二醇盐等[2]。NO供体还能和药物分子偶联形成NO供体型化合物,使     

NCX-4016 NicOx

NCX-4016 is a nitric oxide-aspirin conjugate non-steroidal anti-inflammatory drug that is under investigation by NicOx for the potential treatment of cardiovascular disorders and colon cancer. In April 2002, a phase II clinical trial was initiated in symptomatic peripheral arterial disease, and in March 2003, the University of Michigan was awarded a grant by the NIH to conduct a phase II trial in individuals at risk of colon cancer.     

NCX-4016 NicOx SA

NCX-4016, a nitric oxide non-steroidal anti-inflammatory drug (NO-NSAID) which can inhibit cyclooxygenase as well as release nitric oxide, is under development by NicOx as a potential treatment for thrombosis, inflammation and rheumatoid arthritis. It is an aspirin-nitrobutyl ester and is in phase I clinical trials as an oral antithrombotic agent in the UK [222690]. A placebo-controlled, double-blind study has been completed, which demonstrated good tolerability to NCX-4016. Studies to evaluate pharmacodynamic parameters and gastric tolerability are in progress [275922]. This compound has demonstrated a wider efficacy and tolerability than aspirin under several experimental conditions [210800]. In vitro studies have demonstrated the ability of NCX-4016 to interfere with platelet aggregation, adhesion and thromboxane B2 production. Studies in rats have also demonstrated the biological activity and gastrointestinal safety of NCX-4016 [275922]. NicOx applied for patent coverage in May 1994 and WO-09716405 specifically covers nitrated phenol esters of aspirin. NicOx specializes in the field of nitric oxide donors as therapeutic agents. The company's strategy is based on the development of new proprietary anti-inflammatory, analgesic and antithrombotic drugs with improved gastric and renal safety profiles. NicOx works with a network of outside collaborators from academia and the pharma-ceutical industry, thereby enabling rapid development whilst maintaining only a small infrastructure. The company has raised $7 million, with new investors, including Paribas Principal Investments (France) and Health Corp AB (Sweden) [273176]. The funds will be used to expand its preclinical and clinical research. NicOx is collaborating with Bayer on the development of NCX-4016, and research with other "nitro-aspirins" [281704].     

Nitric oxide-modulating agents for gastrointestinal disorders

Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO–non-steroidal anti-inflammatory drugs (NO–NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed. These have been shown to exhibit reduced gastrointestinal injury in experimental models, and reports on their efficacy and safety in Phase I and II studies are now available. Modulation of the inducible NO synthase isoform that generates excessive NO that can lead to subsequent cytotoxic moieties, such as peroxynitrite, may have therapeutic possibilities in a range of inflammatory diseases of the gut. Likewise, agents that promote the decomposition of peroxynitrite or removal of its other component, superoxide, may also prove to be of use. Further targets for pharmaceutical exploitation are likely to come from both genomic and molecular insights into the processes that regulate the NO system.     

(2-乙酰氧基)苯甲酸(3-硝氧甲基)苯酯的合成工艺改进

以阿司匹林为起始原料,在二环己基碳二亚胺(DCC)和4-二甲胺基吡啶(DMAP)存在下,与间羟基苯甲醇进行酯化反应,生成(2-乙酰氧基)苯甲酸(3-羟甲基)苯酯,再经硝化反应得目标化合物NCX-4016.此法较文献报道的方法操作及后处理简单,收率由60%左右提高到68%.     

Prevention of postischemic myocardial reperfusion injury by the combined treatment of NCX-4016 and Tempol

Nitric oxide (NO) plays a protective role in myocardial ischemia-reperfusion (I/R) injury. However, the concomitant production of superoxide and other reactive oxygen species (ROS) during I/R may diminish the bioavailability of NO and hence compromise the beneficial effects. The objective of this study was to investigate the protective effect of the coadministration of NCX-4016 [2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester] (an NO donor) with antioxidants Tempol, superoxide dismutase (SOD), or urate on I/R injury. Isolated rat hearts, perfused with Krebs-Henseleit buffer, were subjected to 30 minutes of global ischemia, followed by 45 minutes of reperfusion. Before the induction of ischemia, the hearts were infused for 1 minute with NCX-4016 (100 microM) either alone or in combination with Tempol (100 microM), SOD (200 U/mL), or urate (100 microM). Hearts pretreated with NCX-4016 showed a significantly enhanced recovery of function and decreased infarct size and LDH/CK release compared with the controls. However, treatment of hearts with NCX-4016 + Tempol, SOD, or urate showed a significantly enhanced recovery of heart function compared with NCX-4016 alone. The treatment of hearts with NCX-4016 + Tempol showed significantly enhanced NO generation and decreased ROS and dityrosine (a marker of peroxynitrite) formation. In conclusion, NCX-4016 in combination with Tempol demonstrated significant cardioprotection and, thus, may offer a novel therapeutic strategy to prevent I/R-mediated myocardial injury.     

In vitro metabolism of a nitroderivative of acetylsalicylic acid (NCX4016) by rat liver: LC and LC–MS studies

The metabolism of a nitroderivative of acetylsalicylic acid, benzoic acid, 2-(acetyloxy)-3-[(nitrooxy)methyl]phenyl ester (NCX4016), the lead compound of a new class of NO-releasing non steroidal-antiinflammatory drugs has been studied in vitro in rat liver subcellular fractions (S 9000×g, microsomes, cytosol). Samples were extracted with CH₃CN (2 vol.) containing 1% H₃PO₄ (2 M), vortexed for 3 min and then centrifuged for 5 min at 5000 rpm. Supernatants were diluted with 0.02 M phosphoric acid and analysed by reverse-phase LC. Linearity of calibration for NCX4016 and metabolites was observed over the range 0.25–50 μg/ml with coefficients of determination greater than 0.9996. Extraction efficiency from spiked liver samples ranged from 85 to 95% for all the analytes. In the S 9000×g fraction, NCX4016 undergoes rapid metabolization, with the formation of salicylic acid (SA) and [3-(nitrooxymethyl)phenol] (HBN). HBN is then rapidly metabolised to 3-hydroxybenzylalcohol (HBA), and mainly to a new metabolic species, whose formation takes place specifically in the liver cell cytosol. LC–MS analysis (electrospray ionisation) of the cytosol extract in negative and positive-ion modes furnished deprotonated [M−H]⁻ and protonated [M+H]⁺ molecular ions at m/z 412 and 414, respectively, accompanied by the typical clusters with sodium. MS/MS analysis in negative-ion mode, by selection and collision of the ion at m/z 412, gave a fragmentation pattern characterized by the ions at m/z 272 and 254, which allowed to assign the structure of 1-(glutathion-S-yl)methylene-3-hydroxy-benzene, a conjugated product between GSH and the benzyl carbon atom of HBN. In rat liver cytosol HBN is completely metabolised to this thioether adduct within 30 min incubation; the process is enzymatically mediated by GSH transferase and strictly dependent on GSH availability. The relevance of this new metabolic pathway in NCX4016 detoxification by rat liver is discussed.     

Nitric oxide-releasing aspirin inhibits vasoconstriction in perfused tail artery of normotensive and spontaneously hypertensive rats

The aim of this study was to investigate the capacity of the 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX 4016), a nitric oxide (NO)-releaser derivative of aspirin, to decrease blood pressure in spontaneously hypertensive rats (SHR) and to counteract the adrenergic vasoconstriction in perfused tail artery of these animals. Oral treatment for 10 consecutive days with NCX 4016 (100 micromol/kg) in SHR and their genetic controls Wistar Kyoto (WKY) rats resulted in a reduction of blood pressure in SHR but not in WKY rats. In SHR, the NCX 4016 treatment increased the serum nitrite/nitrate and diminished the serum thromboxane B2, whereas aspirin did not change blood pressure but abolished the serum thromboxane B2. Perfused tail arteries excised from vehicle-treated SHR exhibited a significant impairment of endothelium-dependent vasorelaxant function. These vessels, prepared from SHR or WKY rats treated orally with NCX 4016 (10, 30 and 100 micromol/kg for 7 consecutive days), revealed a dose-dependent decrease in vasoconstriction in response to transmural nerve stimulation and norepinephrine, whereas aspirin was ineffective. Furthermore, in tail arteries of both SHR and WKY rats treated orally with NCX 4016 (100 micromol/kg for 7 consecutive days), the cGMP increased significantly. In conclusion, NCX 4016, by releasing NO and increasing cGMP in vascular tissue, reduces sympathetic-mediated vasoconstriction in resistance vessels and lowers blood pressure in SHR.     

Nitric oxide-donating aspirin (NCX 4016): an overview of its pharmacological properties and clinical perspectives

In more than a century of use, the benefits of aspirin have been exploited in different therapeutic areas, from inflammation to cardiovascular disease for which it is an approved treatment for acute coronary heart disease and a recommended treatment for secondary cardiovascular prevention in patients at risk. Nitric oxide (NO), a small gaseous free radical molecule, is an important messenger of cellular and biological function that demonstrates an interesting anti-inflammatory profile and vascular protective activity. In addition, NO exerts a protective action on the gastrointestinal mucosa. An elegant approach for exploiting the properties of both aspirin and NO, and for eventually increasing the overall activity of aspirin, has been to create a new molecule in which aspirin and a NO-donating group are covalently linked (NCX 4016). This molecule requires enzymatic metabolism to release both components in order to provide simultaneous actions. NCX 4016 has been shown to retain the anti-inflammatory properties of aspirin and therefore possesses the same efficacy as aspirin in animal models of pain and inflammation. In addition, the release of NO accounts for the inhibition of the release of some cytokines. In cardiovascular models, NCX 4016 shows a better efficacy than aspirin in counteracting thromboembolism, myocardial infarction and vascular reactivity and remodelling (restenosis). This review describes the pharmacological profile of the NO-donating aspirin, NCX 4016, by addressing principally the pharmacological activity in inflammation and cardiovascular models. Gastrointestinal safety is specifically addressed. The potential clinical use of NCX 4016 in vascular pathologies is also discussed.

     

一氧化氮:理论与新药开发

目的 :一氧化氮为重要的生物学活性物质 ,参与多种信息的传导 ,引起广泛的效应 ,故应深入研究和开发。方法 :临床以一氧化氮用于治疗某些疾病 ,已取得明显而确切的治疗数据。结果与结论 :围绕NO开发用于治疗心血管、肺、神经系统、消化系统疾病及癌症、性功能不全的药物可能成为医学研究的热点 ;随着研究的不断深入 ,它的应用范围将更加广泛     

NCX-1000的新合成方法

[目的]改进NCX-1000的合成方法。[方法]以阿魏酸为原料，在N，N-二甲基甲酰胺或在丙酮中与1，4-二溴丁烷反应得重要中间体3-(4-羟基-3-甲氧苯基)-2-丙烯酸-4-溴丁酯，再与熊去氧胆酸成酯，最后与硝酸银反应得目的物。[结果]所得目的物经红外、质谱、核磁鉴定，其结构与文献报道一致，总收率由文献报道的32％提高至40％。[结论]新的合成工艺所用试剂毒性小，价格低，且反应时间短，操作简便。