STRUCTURE-ACTIVITY RELATION SHIPS OF UK-2a, A NOVEL ANTIFUNGAL ANTIBIOTIC FROM Streptomyces sp.517-02

UK-2a（一种来自链霉菌属 sp.517-02 的新型抗真菌抗生素）的结构-活性关系

• 批准号: 14580615
• 负责人: USUKI Yoshinosuke
• 金额: $ 2.3万
• 依托单位: OSAKA CITY UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580615/
• 关键词: structure-activity relationship; antifungal activity; respiratory inhibition; 9-membered dilactone; 活性酸素種

UK-2A is a novel antifungal antibiotic isolated from Streptomyces sp. 517-02, and is similar to antimycin A3 (AA) in both structure, and inhibitory activity towards electron transport at complex III in mitochondria. However, UK-2A was less cytotoxic than AA in several mammalian cell lines. Because both UK-2A and AA inhibited mitochondrial electron transport, the difference in cytotoxicity could be attributed to differences in production of reactive oxygen species (ROS), accounting for the mechanism of the low cytotoxcity of UK-2A, which is its most prominent effect characteristic.In our studies into establishing structure-activity relationships among UK-2A analogues, a series of hybrid molecules combining structural features of both UK-2A and AA were synthesized to evaluate the inhibitory activity for the uncoupler stimulated respiration of bovine heart SMP and the cytotoxic activity. A hybrid, which was prepared with the 9-membered dilactone residue of UK-2A and the 3-formylaminosalic … More ylic moiety of AA, showed the respiratory inhibition as much as UK-2A or AA and demonstrated also some extent of low cytotoxcity as UK-2A. Preliminary studies on the application of these hybrids for agricultural chemicals were carried out.Other analogous compounds in which the nine-membered dilactone residue was replaced with several alkyl or isoprenyl moieties were prepared. C9-UK-2A, substituted the dilactone ring of UK-2A with n-nonyl moiety, showed the most potent and durable antifungal activities among these derivatives. It's mode of action against two yeasts, Rhodotorula mucilaginosa IFO 0001(RM) and Saccharomyces cerevisiae IFO 0203 (SC) was examined. C9-UK-2A demonstrated a cidal effect to the growth inhibition of RM with membrane injury. On the other hand, C9-UK-2A inhibited the respiration and induced the production of ROS in whole cells as well as intact mitochondria of SC. The growth inhibition of SC induced by C9-UK-2A would depend on the oxidative stress caused by excessive ROS production. Less

UK-2A 是一种从链霉菌中分离出来的新型抗真菌抗生素。 517-02，在结构和对线粒体复合物 III 电子传递的抑制活性方面与抗霉素 A3 (AA) 相似。然而，在几种哺乳动物细胞系中，UK-2A 的细胞毒性低于 AA。由于UK-2A和AA均抑制线粒体电子传递，因此细胞毒性的差异可归因于活性氧（ROS）产生的差异，这解释了UK-2A低细胞毒性的机制，这是其最突​​出的作用特征。在我们建立UK-2A类似物之间结构-活性关系的研究中，一系列结合了两者结构特征的杂化分子 合成UK-2A和AA以评价解偶联剂刺激牛心脏SMP呼吸的抑制活性和细胞毒活性。由 UK-2A 的 9 元双内酯残基和 AA 的 3-甲酰氨基水杨酸部分制备的杂化物显示出与 UK-2A 或 AA 一样多的呼吸抑制作用，并且还表现出与 UK-2A 相同程度的低细胞毒性。对这些杂化物在农用化学品中的应用进行了初步研究。制备了九元双内酯残基被多个烷基或异戊二烯基部分取代的其他类似化合物。 C9-UK-2A用正壬基部分取代UK-2A的双内酯环，在这些衍生物中表现出最有效和持久的抗真菌活性。研究了它针对两种酵母菌（粘液红酵母 IFO 0001(RM) 和酿酒酵母 IFO 0203 (SC)）的作用方式。 C9-UK-2A 对膜损伤的 RM 生长抑制具有杀伤作用。另一方面，C9-UK-2A 抑制 SC 的呼吸并诱导整个细胞以及完整线粒体中 ROS 的产生。 C9-UK-2A 诱导的 SC 生长抑制取决于过量 ROS 产生引起的氧化应激。较少的

项目成果

Y.Usuki, K.Goto, T.Kiso, K.Tani, X.Ping, K.-I.Fujita, H.Iio, M.Taniguchi: "UK-2A, B, C, and D, Novel Antifungal Antibiotics from Streptomyces sp. 517-02 VI(2). Structure-Activity Relationships of UK-2A"The Journal of Antibiotics. 55(6). 607-610 (2002)

Y.Usuki、K.Goto、T.Kiso、K.Tani、X.Ping、K.-I.Fujita、H.Iio、M.Taniguchi：“UK-2A、B、C 和 D，新型抗真菌抗生素

K.Tani, Y.Usuki, K.-I.fujita, M.Taniguchi: "UK-2A, B, C, and D, Novel Antifungal Antibiotics from Streptomyces sp. 517-02. VIII. Reactive Oxygen Species Generated by C9-UK-2A, a Derivative of UK-2A, in Rhodotorula mucilaginosa IFO 0001"The Journal of Anti

K.Tani、Y.Usuki、K.-I.fujita、M.Taniguchi：“UK-2A、B、C 和 D，来自链霉菌属的新型抗真菌抗生素。517-02。VIII. C9 产生的活性氧

K.-I.Fujita, K.Tani, Y.Usuki, T.Tanaka, M.Taniguchi: "UK-2A, B, C and D, Novel Antifungal Antibiotics from Streptomyces sp.517-02 IX. Growth Inhibition Dependent on Reactive Oxygen Species Generated by C9-UK-2A, a derivative of UK-2A, in Saccharomyces cer

K.-I.Fujita、K.Tani、Y.Usuki、T.Tanaka、M.Taniguchi：“UK-2A、B、C 和 D，来自链霉菌 sp.517-02 的新型抗真菌抗生素 IX。生长抑制取决于

Y.Usuki, K.Goto, T.Kiso, K.Tani, X.Ping, K.-I.Fujita, H.Iio, M.Taniguchi: "UK-2A, B, C and D, Novel Antifungal antibiotics from streptomyces sp. 517-02 VI(2). Structure-Activity Relationships of UK-2A"The Journal of Antibiotics. 55(6). 607-610 (2002)

Y.Usuki、K.Goto、T.Kiso、K.Tani、X.Ping、K.-I.Fujita、H.Iio、M.Taniguchi：“UK-2A、B、C 和 D，新型抗真菌抗生素

K.Tani, Y.Usuki, K.-I.Fujita, M.Taniguchi: "UK-2A, B, C, and D, Novel Antifungal Antibiotics from Streptomyces sp.517-02 VIII. Reactive Oxygen Species Generated by C9-UK-2A, a Derivative of UK-2A, in Rhodotorula mucilaginosa IFO 0001"The Journal of Antibi

K.Tani、Y.Usuki、K.-I.Fujita、M.Taniguchi：“UK-2A、B、C 和 D，来自链霉菌 sp.517-02 的新型抗真菌抗生素 VIII。C9- 产生的活性氧