Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany; Department of Pharmacognosy, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
Institute of Pharmaceutical Biology and Biotechnology, Faculty of Mathematics and Natural Sciences, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany; Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University Abbassia, 11566 Cairo, Egypt.
Bioorg Med Chem. 2021 Jan 1;29:115883. doi: 10.1016/j.bmc.2020.115883. Epub 2020 Nov 21.
Fermentation of the marine-derived fungus Aspergillus falconensis, isolated from sediment collected from the Red Sea, Egypt on solid rice medium containing 3.5% NaCl yielded a new dibenzoxepin derivative (1) and a new natural isocoumarin (2) along with six known compounds (3-8). Changes in the metabolic profile of the fungus were induced by replacing NaCl with 3.5% (NH)SO that resulted in the accumulation of three further known compounds (9-11), which were not detected when the fungus was cultivated in the presence of NaCl. The structures of the new compounds were elucidated by HRESIMS and 1D/2D NMR as well as by comparison with the literature. Molecular docking was conducted for all isolated compounds on crucial enzymes involved in the formation, progression and metastasis of cancer which included human cyclin-dependent kinase 2 (CDK-2), human DNA topoisomerase II (TOP-2) and matrix metalloproteinase 13 (MMP-13). Diorcinol (7), sulochrin (9) and monochlorosulochrin (10) displayed notable stability within the active pocket of CDK-2 with free binding energy (ΔG) equals to -25.72, -25.03 and -25.37 Kcal/mol, respectively whereas sulochrin (9) exerted the highest fitting score within MMP-13 active center (ΔG = -33.83 Kcal/mol). In vitro cytotoxic assessment using MTT assay showed that sulochrin (9) exhibited cytotoxic activity versus L5178Y mouse lymphoma cells with an IC value of 5.1 µM and inhibition of migration of MDA-MB 231 breast cancer cells at a concentration of 70 µM.
从埃及红海沉积物中分离得到的海洋来源真菌曲霉菌（Aspergillus falconensis）在含 3.5%NaCl 的固体大米培养基中发酵，得到一个新的二苯并[α,e]氧杂环庚烯衍生物（1）和一个新的天然异香豆素（2），以及六个已知化合物（3-8）。用 3.5%（NH）SO 替代 NaCl 会改变真菌的代谢谱，导致另外三个已知化合物（9-11）的积累，而当真菌在含有 NaCl 的情况下培养时，这些化合物没有被检测到。新化合物的结构通过 HRESIMS 和 1D/2D NMR 以及与文献的比较来阐明。对所有分离得到的化合物进行了分子对接，这些化合物针对参与癌症形成、进展和转移的关键酶，包括人细胞周期蛋白依赖性激酶 2（CDK-2）、人 DNA 拓扑异构酶 II（TOP-2）和基质金属蛋白酶 13（MMP-13）。二氢姜黄素（7）、硫辛素（9）和单氯硫辛素（10）在 CDK-2 的活性口袋内显示出显著的稳定性，其自由结合能（ΔG）分别为-25.72、-25.03 和-25.37 Kcal/mol，而硫辛素（9）在 MMP-13 的活性中心具有最高的拟合分数（ΔG=-33.83 Kcal/mol）。使用 MTT 测定法进行的体外细胞毒性评估表明，硫辛素（9）对 L5178Y 小鼠淋巴瘤细胞具有细胞毒性活性，IC 值为 5.1μM，对 MDA-MB 231 乳腺癌细胞的迁移抑制浓度为 70μM。
