Xiao Hua, Wang Guiyang, Wang Zhengdong, Kuang Yi, Song Juan, Jin Jing, Ye Min, Yang Donghui, Ma Ming
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
Molecules. 2021 Mar 31;26(7):1959. doi: 10.3390/molecules26071959.
Angucyclinones are aromatic polyketides that possess impressive structural diversity and significant biological activities. The structural diversity of these natural products is attributed to various enzymatic or nonenzymatic modifications on their tetracyclic benz()anthracene skeleton. Previously, we discovered an unusual phenylamine-incorporated angucyclinone () from a marine sp. PKU-MA00218, and identified that it was produced from the nonenzymatic conversion of a C-ring-cleaved angucyclinone () with phenylamine. In this study, we tested the nonenzymatic conversion of with more phenylamine analogues, to expand the utility of this feasible conversion in unusual angucyclinones generation. The (3-ethynyl)phenylamine and disubstituted analogues including (3,4-dimethyl)phenylamine, (3,4-methylenedioxy)phenylamine, and (4-bromo-3-methyl)phenylamine were used in the conversion of , which was isolated from the fermentation of sp. PKU-MA00218. All four phenylamine analogues were incorporated into efficiently under mild conditions, generating new compounds -. The activation of - on nuclear factor erythroid 2-related factor 2 (Nrf2) transcription were tested, which showed that possessing a dimethyl-substitution gave most potent activity. These results evidenced that disubstitutions on phenylamine can be roughly tolerated in the nonenzymatic reactions with , suggesting extended applications of more disubstituted phenylamines incorporation to generate new bioactive angucyclinones in the future.
安古环素类化合物是一类芳香族聚酮化合物，具有令人瞩目的结构多样性和显著的生物活性。这些天然产物的结构多样性归因于其四环苯并（）蒽骨架上的各种酶促或非酶促修饰。此前，我们从海洋 菌株PKU-MA00218中发现了一种不同寻常的含苯胺安古环素（），并确定它是由一种C环裂解的安古环素（）与苯胺发生非酶促转化生成的。在本研究中，我们用更多苯胺类似物测试了 的非酶促转化，以扩大这种可行转化在生成不同寻常的安古环素类化合物中的应用。（3-乙炔基）苯胺和二取代类似物，包括（3,4-二甲基）苯胺、（3,4-亚甲二氧基）苯胺和（4-溴-3-甲基）苯胺被用于 的转化， 是从 菌株PKU-MA00218的发酵产物中分离得到的。在温和条件下，所有四种苯胺类似物都能有效地掺入到 中，生成新的化合物 - 。测试了 - 对核因子红细胞2相关因子2（Nrf2）转录的激活作用，结果表明具有二甲基取代的 具有最强的活性。这些结果证明，在与 的非酶促反应中，苯胺上的二取代大致是可以耐受的，这表明未来更多二取代苯胺的掺入在生成新的生物活性安古环素类化合物方面有更广泛的应用。
