College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, PR China.
College of Life Science, Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou University, Huzhou 313000, PR China.
Bioorg Chem. 2022 Feb;119:105573. doi: 10.1016/j.bioorg.2021.105573. Epub 2021 Dec 16.
Tetrodecadazinone (1), a novel tetrodecamycin-pyridazinone hybrid possessing a new 1,2-dimethyl-1-(2-methylnonyl)decahydronaphthalene skeleton, and 4-hydroxydihydrotetrodecamycin (2) were separated from a culture of Streptomyces sp. HU051, together with a known compound, dihydrotetrodecamycin (3). Diverse spectroscopic approaches were applied to assign the structures of 1-3, and the structure of 1 was further confirmed by single crystal X-ray diffraction analysis. Compound 1 is the first example of a pyridazinone-containing natural product. Biosynthetically, 1 is proposed to be derived from a Michael addition reaction of a PKS-derived tetrodecamycin and a piperazic-acid-derived pyridazinone. Biological evaluation revealed 1 could reduce the expressions of extracellular matrix proteins (fibronectin and collagen I) and α-smooth muscle actin (α-SMA) in transforming growth factor-β (TGF-β1)-activated LX-2 cells. Preliminary mechanism study showed 1 exerted its anti-liver fibrosis effect by regulating TGF-β1/Smad2/3 signaling pathway.
特托迪卡嗪酮（1），一种新型的四环达马嗪-哒嗪酮杂合体，具有全新的 1,2-二甲基-1-(2-甲基壬基)十氢萘骨架，以及 4-羟二氢四环达马嗪（2），是从链霉菌属 HU051 的培养物中分离出来的，此外还有一种已知化合物，二氢四环达马嗪（3）。多种光谱方法被应用于确定 1-3 的结构，并且 1 的结构通过单晶 X 射线衍射分析进一步得到证实。化合物 1 是第一个含有哒嗪酮的天然产物。从生物合成的角度来看，1 被认为是由 PKS 衍生的四环达马嗪和哌嗪酸衍生的哒嗪酮之间的迈克尔加成反应形成的。生物评价显示，1 可降低转化生长因子-β (TGF-β1) 激活的 LX-2 细胞中外基质蛋白（纤维连接蛋白和胶原蛋白 I）和 α-平滑肌肌动蛋白 (α-SMA) 的表达。初步的机制研究表明，1 通过调节 TGF-β1/Smad2/3 信号通路发挥其抗肝纤维化作用。
