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     

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。     

苯磺酰基呋咱氮氧化物与双氯芬酸偶联化合物的合成及抗炎活性

目的　研究高效低毒的双氯芬酸 (DC)偶联化合物。方法　以酯键或酰胺键将一氧化氮 (NO)供体 3 ,4 二苯磺酰基呋咱氮氧化物与DC偶联 ,观察偶联物对二甲苯致炎小鼠和角叉菜胶致炎大鼠的抗炎活性及对大鼠胃肠道反应 ,研究体内外偶联物的NO释放。结果　合成了 11个新化合物 (I1 - 1 1 ) ,其结构经MS ,IR ,1 HNMR和元素分析确证。I1 - 5,I9显示抗炎活性 ,其中I4 和I5活性与DC相当 ,胃肠道副作用显著小于DC ,体内外均释放NO。结论　苯磺酰基呋咱氮氧化物与DC偶联的化合物可保留DC抗炎活性 ,降低DC胃肠道不良反应。     

一氧化氮供体型非甾体抗火药的研究

一氧化氮是生物体内重要的信使分子和效应分子，参与多种生理功能的调节，在胃肠道系统中具有保护胃粘膜的作用，将一氧化氮供本引入到传统的非甾体抗炎药结构中是近年来解决传统非甾体抗炎药胃肠道副作用问题的热点之一。本文就近年来一氧化氮供体型非甾体抗炎药的研究情况作一简要综述。     

α-常春藤皂苷一氧化氮供体衍生物的合成及其抗肿瘤活性研究

目的合成并表征α-常春藤皂苷一氧化氮供体衍生物,并对其抗肿瘤活性进行研究。方法采用苯硫酚作为起始原料,以不同长度的二醇作为连接臂,将α-常春藤皂苷的28位羧基和呋咱氮氧化物连接在一起得到α-常春藤皂苷一氧化氮供体衍生物;并采用MTT法对目标化合物进行体外抗乳腺癌活性研究。结果合成了4个α-常春藤皂苷一氧化氮供体衍生物,其结构均通过1H-NMR和MS确证。生物活性结果测试表明其抗肿瘤活性均优于阳性对照药α-常春藤皂苷。结论α-常春藤皂苷一氧化氮供体衍生物抗肿瘤活性明显,具有很好的开发价值。     

苯磺酰基呋咱氮氧化物与双氯芬酸偶联化合物的合成及抗炎活性

目的　研究高效低毒的双氯芬酸(DC)偶联化合物。方法　以酯键或酰胺键将一氧化氮(NO)供体3 ,4-二苯磺酰基呋咱氮氧化物与DC偶联,观察偶联物对二甲苯致炎小鼠和角叉菜胶致炎大鼠的抗炎活性及对大鼠胃肠道反应,研究体内外偶联物的NO释放。结果　合成了11个新化合物(I_1-11) ,其结构经MS ,IR ,¹HNMR和元素分析确证。I_1-5,I₉显示抗炎活性,其中I₄ 和I₅活性与DC相当,胃肠道副作用显著小于DC ,体内外均释放NO。结论　苯磺酰基呋咱氮氧化物与DC偶联的化合物可保留DC抗炎活性,降低DC胃肠道不良反应。     

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     

一氧化氮供体最新研究进展及应用前景

一氧化氮供体已经成为当今药物研究中的一大焦点,此文对近年来一氧化氮供体研究领域的最新研究成果作一综述,并展望了其在医疗上的应用前景。     

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。     

α-常春藤皂苷一氧化氮供体衍生物的合成及其抗肿瘤活性研究

目的合成并表征α-常春藤皂苷一氧化氮供体衍生物,并对其抗肿瘤活性进行研究。方法采用苯硫酚作为起始原料,以不同长度的二醇作为连接臂,将α-常春藤皂苷的28位羧基和呋咱氮氧化物连接在一起得到α-常春藤皂苷一氧化氮供体衍生物;并采用MTT法对目标化合物进行体外抗乳腺癌活性研究。结果合成了4个α-常春藤皂苷一氧化氮供体衍生物,其结构均通过1H-NMR和MS确证。生物活性结果测试表明其抗肿瘤活性均优于阳性对照药α-常春藤皂苷。结论α-常春藤皂苷一氧化氮供体衍生物抗肿瘤活性明显,具有很好的开发价值。     

Dual COX-inhibitors: the answer is NO?

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of anti-inflammatory agents obtained by adding an NO releasing moiety to existing NSAIDs. They have also christened as COX inhibiting NO-donating drugs (CINOD). Preclinical and clinical studies suggest that CINOD inhibit COX-1 and COX-2 activities while cause less adverse effects on gastrointestinal tract in comparison to conventional NSAIDs and coxibs and reduce systemic blood pressure. A different class of NO-donating drugs has been obtained by coupling NO to aspirin. These NO-releasing aspirins are new chemical entities that maintain and possibly expands the pharmacological properties of aspirin, but spare the gastrointestinal mucosa. Animal studies have shown that CINOD and NO-aspirins maintain gastric mucosal blood flow and reduce leukocyte-endothelial cell adherence.     

Therapeutic potential of nitrate esters of commonly used drugs

Organic nitrates, such as nitroglycerin, have been used in clinical practice for more than one century for the treatment of angina, even before the identification of Nitric Oxide (NO) as the so-called Endothelium Derived Relaxing Factor (EDRF). Recently, multiple functions of this molecule in biology and pathophysiology have been discovered and alterations in the NO signalling pathway have often been associated with disease progression in mammals, providing a strong rationale for the use of NO as a potential drug. To have a therapeutic benefit from NO properties, an elegant approach has been designed coupling well-known existing drugs with moieties able to slowly release NO following enzymatic metabolism. "Hybrid nitrates", in which activities of both the native drug and NO are present, have been obtained with the aim of originating safer and more active drugs. The technology consists in the choice of the appropriate chemical spacer arm carrying the nitric ester in order to obtain the best pharmacodynamic and pharmacokinetic profile. The connecting linkers already explored are of different chemical structure, ranging from aliphatic chains to heteroaromatic rings. The molecules so far obtained have already demonstrated their potential therapeutic interest in both pharmacological tests and clinical trials. In this review, we describe the approach and the possibility of generating new chemical entities, combining well-known drugs with an NO-donating moiety in order to increase activity and safety, along with examples of their activity and potential therapeutic application in different pathologies. A few significant examples of molecules in the early preclinical stage, as well as in advanced clinical development will be described.     

噁三唑类NO供体型他汀衍生物的合成及活性评价

目标 合成系列噁三唑类NO供体型他汀衍生物并进行体外活性评价。方法 选用噁三唑类NO供体分别与阿托伐他汀和辛伐他汀通过酯化进行偶联。结果 设计合成了5个噁三唑类NO供体和5个该类NO供体型他汀衍生物。结论 通过部分目标化合物体外活性测定,表明它们具有良好的NO释放活性。     

FK409类NO供体型他汀衍生物合成及活性评价

目的 合成系列FK409类NO供体型他汀衍生物并进行体外活性评价。方法 本文选用FK409类NO供体与阿托伐他汀、匹伐他汀及瑞舒伐他汀3种他汀药物分别通过酯化进行偶联。结果 设计合成了2个FK409类NO供体和6个该类NO供体型他汀衍生物。结论 通过体外活性测定,目标化合物具有良好的NO释放活性。     

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs: novel gastrointestinal-sparing drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.     

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.

     

Nitrosothiol esters of diclofenac: synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs

Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.     

一氧化氮供体修饰非甾体类抗炎药研究进展

非甾体类抗炎药(NSAID)有严重的胃肠道和心血管系统的不良反应。一氧化氮(NO)作为体内重要的信使物质,具有保护胃粘膜和心血管系统的作用。将NO的药理学特性用于对抗NSAID的不良反应,从而出现了一氧化氮供体非甾体类抗炎药(NO-NSAID)。本文介绍NO-NSAID在治疗炎症、癌症、阿尔茨海默病和糖尿病中的应用。     

Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential

The discovery of the multiple physiological and pathophysiological processes in which nitric oxide (NO) is involved has promoted a great number of pharmacological researches to develop new drugs that are capable of influencing NO production directly and/or indirectly for therapeutic purposes (i.e, NO-releasing drugs, NO-inhibiting drugs, and phosphodiesterase V inhibitors). In particular, the so-called NO donor drugs could actually have an important therapeutic effect in the treatment of many diseases such as arteriopathies (atherosclerosis and its sequelae, arterial hypertension and some forms of male sexual impotence), various acute and chronic inflammatory conditions (colitis, rheumatoid arthritis and tissue remodelling), and several degenerative diseases (Alzheimer’s disease and cancer). The old organic nitrates show some well-known pitfalls including the induction of tolerance and acute side effects related to abrupt vasodilation such as cephalea and hypotension, which limit their therapeutic indications. A low therapeutic index (i.e., peroxynitrite toxicity) has always characterised the sydnonimines class. A series of interesting new classes of NO donors are under intense pharmacological investigation and scrutiny (S-nitrosothiols, diazeniumdiolates and NO hybrid drugs), each characterised by a particular pharmacokinetic and pharmacodynamic profile. The most important obstacle in the field of NO donor drugs is represented by the difficulty in targeting NO release, and thereby its effects, to a particular tissue.     

Nitric oxide and the gut injury induced by non-steroidal anti-inflammatory drugs

Nitric oxide (NO) can protect the gastrointestinal tract from injury, including that provoked by non-steroidal anti-inflammatory drugs (NSAIDs). This protective profile of NO, which predominantly reflects actions on the microcirculation, is mimicked by NO donors. Moreover, the NO-donating agents know as the NO-NSAIDs or CINODs (cyclo-oxygenase-inhibiting nitric oxide-donating drugs) exhibit reduced gut injury in experimental models, which is considered to reflect these local beneficial actions of NO. NSAIDs cause chronic inflammatory lesions in the small intestine in experimental models. This injury results from initial COX inhibition and other local events, with translocation of indigenous luminal bacteria, leading to induction of NO synthase isoform, iNOS, and subsequent production of the cytotoxic moiety, peroxynitrite from NO and superoxide. Agents that inhibit iNOS or superoxide production can attenuate such intestinal injury. In the absence of reactive oxygen moieties, NO may play a beneficial role in the resolution of inflammatory damage to the gut, thus reconciling the potential opposing properties of NO in tissue inflammation and injury.