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

UK-2A是从链霉菌中分离得到的一种新型抗真菌抗生素。517-02，在结构上与抗霉素A3(AA)相似，对线粒体复合体III的电子传递有抑制作用。然而，在一些哺乳动物细胞系中，UK-2A的细胞毒性低于AA。由于UK-2A和AA都抑制线粒体电子传递，细胞毒性的差异可能归因于活性氧自由基(ROS)产生的差异，这是UK-2A最显著的作用特征之一。在建立UK-2A类似物之间的构效关系的研究中，我们合成了一系列结合UK-2A和AA的结构特征的杂化分子，以评价其对解偶联剂刺激的牛心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3-甲酰氨基水杨酸…制备的杂交物其呼吸抑制作用与UK-2A或AA相当，也表现出一定程度的低细胞毒作用。对这些杂化化合物在农用化学品中的应用进行了初步的研究，合成了其他类似的化合物，其中九元双内酯残基被几个烷基或异戊二烯取代。在这些衍生物中，C9-UK-2A用正壬基取代了UK-2A的双内酯环，显示出最有效和持久的抗真菌活性。对粘红酵母IFO 0001(RM)和酿酒酵母IFO 0203(SC)两种酵母菌进行了抑菌实验。C9-UK-2A对膜损伤的RM生长抑制有明显的杀伤作用。另一方面，C9-UK-2A抑制了SC的呼吸，诱导了整个细胞和完整线粒体中ROS的产生。C9-UK-2A对SC的生长抑制作用可能依赖于过量产生ROS所引起的氧化应激。较少

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