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

UK-2A是从链霉菌（Streptomycessp.517 -02）中分离得到的一种新的抗真菌抗生素，其结构与抗霉素A3（antimycinA 3，AA）相似，对线粒体复合体Ⅲ的电子传递具有抑制活性。然而，UK-2A在几种哺乳动物细胞系中的细胞毒性低于AA。由于UK-2A和AA均能抑制线粒体电子传递，因此，活性氧（ROS）产生的差异可能是导致UK-2A细胞毒性低的主要原因。合成了一系列结合UK-2A和AA结构特征的杂合分子，以评价其对解偶联剂刺激的牛心脏SMP呼吸的抑制活性和细胞毒性活性。用UK-2A的9-元双内酯残基和3-甲酰氨基水杨酸 ...更多信息 AA的环状结构部分对呼吸道的抑制作用与UK-2A或AA相当，但其细胞毒性也比UK-2A低。对这些杂环化合物在农药中的应用进行了初步研究，并合成了其它类似的化合物，其中九元双内酯残基被几个烷基或异戊二烯基取代。其中C9-UK-2A是在UK-2A的双内酯环上用壬基取代而得到的，具有最强的抗真菌活性。研究了它对粘红酵母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的生长抑制具有杀灭作用。另一方面，C9-UK-2A可抑制SC的呼吸作用，并诱导整个细胞和完整线粒体产生ROS，C9-UK-2A对SC生长的抑制作用可能依赖于ROS过量产生所引起的氧化应激。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