A practical strategy to discover new antitumor compounds by activating silent metabolite production in fungi by diethyl sulphate mutagenesis.
A practical strategy to discover new antitumor compounds by activating silent metabolite production in fungi by diethyl sulphate mutagenesis.
复制标题
通过硫酸二乙酯诱变激活真菌中沉默代谢产物的产生来发现新的抗肿瘤化合物的实用策略。
DOI：
10.3390/md12041788
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发表时间：
2014-03-27
期刊：
影响因子：
5.4
通讯作者：
Cui CB
中科院分区：
文献类型：
--
作者：
Fang SM;Wu CJ;Li CW;Cui CB
许多真菌生物合成途径在标准培养条件下是沉默的，沉默途径的激活可能能够获得具有抗肿瘤活性的新代谢物。本研究的目的是为微生物化学家制定一种实用策略来获取真菌中的沉默代谢物。我们使用海洋来源的真菌紫青霉 G59 和改良的硫酸二乙酯诱变程序证明了这一策略。利用这一策略，我们发现了四种新的抗肿瘤化合物，分别命名为penicimutanolone (1)、penicimutanin A (2)、penicimutanin B (3) 和penicimutatin (4)。通过光谱方法，特别是广泛的二维核磁共振分析，阐明了新化合物的结构。使用人类癌细胞系通过MTT方法测定抗肿瘤活性。使用生物测定和 HPLC-光电二极管阵列检测器 (PDAD)-UV 和 HPLC-电子喷雾电离 (ESI)-MS 分析来估计活化的次级代谢产物的产生。化合物2和3具有新颖的结构，其中1是一个新化合物，属于一类非常稀有的天然产物，迄今为止仅知道其中的四个成员。化合物1-3对多种人类癌细胞系有抑制作用，IC50值低于20 μM，化合物4对细胞系有一定的抑制作用。这些结果证明了这种通过激活沉默真菌代谢途径来发现新化合物的策略的有效性。这些发现为在沉默真菌代谢物研究中增加使用化学诱变策略提供了理论依据。
Many fungal biosynthetic pathways are silent in standard culture conditions, and activation of the silent pathways may enable access to new metabolites with antitumor activities. The aim of the present study was to develop a practical strategy for microbial chemists to access silent metabolites in fungi. We demonstrated this strategy using a marine-derived fungus Penicillium purpurogenum G59 and a modified diethyl sulphate mutagenesis procedure. Using this strategy, we discovered four new antitumor compounds named penicimutanolone (1), penicimutanin A (2), penicimutanin B (3), and penicimutatin (4). Structures of the new compounds were elucidated by spectroscopic methods, especially extensive 2D NMR analysis. Antitumor activities were assayed by the MTT method using human cancer cell lines. Bioassays and HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses were used to estimate the activated secondary metabolite production. Compounds 2 and 3 had novel structures, and 1 was a new compound belonging to a class of very rare natural products from which only four members are so far known. Compounds 1–3 inhibited several human cancer cell lines with IC50 values lower than 20 μM, and 4 inhibited the cell lines to some extent. These results demonstrated the effectiveness of this strategy to discover new compounds by activating silent fungal metabolic pathways. These discoveries provide rationale for the increased use of chemical mutagenesis strategies in silent fungal metabolite studies.
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通过在海洋来源的紫青霉 G59 中引入庆大霉素抗性来激活休眠的次生代谢产物生产
影响因子：
5.4
作者：
Chai YJ;Cui CB;Li CW;Wu CJ;Tian CK;Hua W
通讯作者：
Hua W
影响因子：
1.7
作者：
Gomes, Nelson M.;Dethoup, Tida;Kijjoa, Anake
通讯作者：
Kijjoa, Anake
影响因子：
3.8
作者：
Kimura, Y;Tani, K;Shimada, A
通讯作者：
Shimada, A
影响因子：
3.6
作者：
BARROW, CJ;CAI, P;COOPER, R
通讯作者：
COOPER, R
影响因子：
14.8
作者：
Bergmann, Sebastian;Schuemann, Julia;Hertweck, Christian
通讯作者：
Hertweck, Christian