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Development of novel oxyl-radical quenching pharmacophores as drug candidates

开发新型氧自由基猝灭药效团作为候选药物

基本信息

批准号：
14370763
负责人：
MIYATA Naoki
金额：
$ 8.58万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14370763/
关键词：
oxyl radical radical scavenger active oxygen species pharmacophore fullerene catechin edaravone tocopherol オキシラジカル ESR スピントラップ剤神経毒性

项目摘要

Development of antioxidants for the treatment of diseases associated with oxidative stress is being interested. In this research project, we intended to find novel oxyl-radical quenching pharmacophores as drug candidates.1.To utilize an antioxidant property of fullerene in organic solvent, we designed and synthesized water-soluble fullerenes, and found their effective reactive-oxygen-species(ROS)quenching activity in aqueous solvents. Water-soluble fullerene protected Parkinson's disease-like cell damages caused by MPP+.2.Planar catechin analogues, in which the catechol and chroman structure in catechin was constrained to be planar, were designed and synthesized. Their enhanced antioxidant property was established by ESR spectrometry. The effective protection of DNA-damage caused by ROS was confirmed by using plasmid DNA.3.Pyrazolone derivatives were designed and synthesized and their antioxidant properties were estimated. A derivative with an intramolecular hydrogen bonding was found … More to be an effective radical scavenger in ESR spin-trapping method.4.A new type of photoinduced nitric oxide(NO)donors was designed from nitrobenzene derivatives. Visible-light irradiation revealed efficient NO-releasing using ESR analysis and Griess assay. NO-releaseing activity was also confirmed in in vitro cell-level experiments.5.Structural basis for DNA-cleaving activity of resveratrol and its analogues were studied and the structure-activity relationship in DNA strand scission was characterized.6.Antioxidants with lipophilic substituent which can be located in cellular membrane were designed and synthesized. Their ROS-scavenging activity in membrane was evaluated by redox potential in liposome and by a protection from oxidative damage of phosphatidylserine moiety in liposomal membrane.These findings obtained by this research project will be useful for development of antioxidants for the treatment of diseases associated with oxidative stress. We are continuing further study on this research to find useful pharmacophores as antioxidants. Less

抗氧化剂的开发用于治疗与氧化应激有关的疾病是很有兴趣的。在本研究项目中，我们打算寻找新的氧自由基猝灭药效团作为候选药物。为了利用富勒烯在有机溶剂中的抗氧化性能，我们设计并合成了水溶性富勒烯，并研究了其在水溶液中的活性氧（ROS）猝灭活性。水溶性富勒烯保护MPP+ 2引起的帕金森病样细胞损伤。设计并合成了平面儿茶素类似物，其中儿茶素中的儿茶素和色氨酸结构被限制为平面结构。ESR光谱法证实其抗氧化性能增强。利用质粒dna证实了对ROS引起的dna损伤的有效保护作用。设计并合成了吡唑酮衍生物，并对其抗氧化性能进行了评价。在ESR自旋捕获法中发现了具有分子内氢键的衍生物，是一种有效的自由基清除剂。以硝基苯衍生物为原料，设计了一种新型光诱导一氧化氮（NO）给体。ESR和Griess实验显示，可见光照射能有效释放no。体外细胞水平实验也证实了no的释放活性。研究了白藜芦醇及其类似物的DNA切割活性的结构基础，并对其在DNA链切割中的构效关系进行了表征。设计并合成了可定位于细胞膜的亲脂取代基抗氧化剂。通过脂质体的氧化还原电位和脂质体膜中磷脂酰丝氨酸部分的氧化损伤保护来评价其在膜中的ros清除活性。本研究结果将有助于开发抗氧化剂，用于治疗与氧化应激有关的疾病。我们正在继续对这一研究进行进一步的研究，以寻找有用的抗氧化剂。少

项目成果

期刊论文数量（62）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Planar Catechin Analogues with Alkyl Side Chains : A Potent Antioxidant and an alpha-Glucosidase Inhibitor

具有烷基侧链的平面儿茶素类似物：一种有效的抗氧化剂和 α-葡萄糖苷酶抑制剂

DOI：
发表时间：
2006
期刊：
Journal of the American Chemical Society 128
影响因子：
0
作者：
W.Hakamata.;I.Nakanishi;Y.Masuda.;T.Shimizu.;H.Higuchi.;Y.Nakamura.;S.Saito.;S.Urano.;T.Oku.;T.Ozawa;N.Ikota;N.Miyata;H.Okuda.;K.Fukuhara.
通讯作者：
K.Fukuhara.

Hiroshi Tokiwa: "Structural activity relationship between Salmonella-mutagenicity and nitro-orientation of nitroazaphenanthrenes"Chemico-Biological Interactions. 146(1). 19-25 (2003)

Hiroshi Tokiwa：“沙门氏菌致突变性与硝基氮杂菲硝基取向之间的结构活性关系”化学-生物相互作用。