背景:Tropolone和泰兰地辛B是天然存在的物质,主要从真菌和植物中分离出来,尽管它们也可以在某些细菌中找到。Tropolones属于一类重要的芳香族化合物,具有七元非苯环结构。Thailandepsin是一组天然产物,最初是在革兰氏阴性细菌Burkholderiathailandensis的培养液中发现的。已经在200多种天然化合物中鉴定了基于托波隆的结构,从简单的托波隆衍生物到复杂的多环系统,如吡啶酮和丙酮酸盐A。这些天然化合物具有多种药理作用,包括抗菌,抗真菌药,杀虫,植物毒性,抗炎,抗有丝分裂,抗糖尿病,酶抑制性,抗癌,细胞保护,和ROS清除特性。值得注意的是,thujaplicane,一种类似于Tropolone的化合物,显示所有列出的生物活性,除了抗有丝分裂作用,这只在一种天然的托波隆化合物中观察到,秋水仙碱.托洛酮可以由市售的七元环合成或通过各种环化和环加成反应衍生。ThailandepsinB,另一方面,可以通过相应的果酸的宏观内酯化合成,随后形成内部二硫键。值得一提的是,与FK228相比,泰兰地辛B表现出不同的选择性抑制谱。
目的:我们研究了Tropolones和ThailandepsinB的HDAC抑制活性,并讨论了天然化合物的生物合成及其合成方案。
结论:已观察到Tropolone衍生物可作为已证明的抗癌药物靶标的同工酶选择性抑制剂,组蛋白脱乙酰酶(HDACs)。一些单取代的对托罗酮显示出对HDAC2的显着选择性水平,并强烈抑制T淋巴细胞细胞系的生长。泰兰地辛与FK228具有不同的选择性抑制谱。它们对人HDAC1、HDAC2、HDAC3、HDAC6、HDAC7和HDAC9表现出与FK228相当的抑制活性,但对HDAC4和HDAC8的抑制活性低于FK228,后者可能是有用的。泰兰地辛对某些类型的细胞系具有有效的细胞毒性活性。
Tropolone and thailandepsin B are naturally occurring substances that are primarily isolated from fungi and plants, although they can also be found in certain bacteria. Tropolones belong to an important class of aromatic compounds with a seven-membered nonbenzenoid ring structure. Thailandepsins are a group of natural products that were initially discovered in the culture broth of the Gram-negative bacterium Burkholderia thailandensis. Tropolonebased structures have been identified in over 200 natural compounds, ranging from simple tropolone derivatives to complex multicyclic systems like pycnidione and pyrerubrine A. These natural compounds exhibit a diverse range of pharmacological effects, including antibacterial, antifungal, insecticidal, phytotoxic, anti-inflammatory, antimitotic, anti-diabetic, enzyme inhibitory, anticancer, cytoprotective, and ROS scavenging properties. It is worth noting that thujaplicane, a compound similar to tropolone, displays all of the listed biological activities except for antimitotic action, which has only been observed in one natural tropolone compound, colchicine. Tropolone can be synthesized from commercially available seven-membered rings or derived through various cyclization and cycloaddition reactions. Thailandepsin B, on the other hand, can be synthesized by macro-lactonization of the corresponding secoacid, followed by the formation of internal disulfide bonds. It is important to mention that thailandepsin B exhibits different selective inhibition profiles compared to FK228.
We investigated the HDAC inhibitory activity of the Tropolones and Thailandepsin B and discussed the biosynthesis of the naturally occurring compounds and their synthetic scheme.
It has been observed that Tropolone derivatives act as isoenzyme-selective inhibitors of proven anticancer drug targets, histone deacetylases (HDACs). Some monosubstituted tropolones show remarkable levels of selectivity for HDAC2 and strongly inhibit the growth of T-lymphocyte cell lines. And Thailandepsins have different selective inhibition profiles than FK228. They exhibit comparable inhibitory activities to FK228 against human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9, but less potent inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which may be useful. Thailandepsins possess potent cytotoxic activities toward some types of cell lines.