Han Jae Sang, Kim Eun-Sook, Cho Yong Beom, Kim Sun Young, Lee Mi Kyeong, Hwang Bang Yeon, Lee Jin Woo
College of Pharmacy, Chungbuk National University, Cheongju 28610, Republic of Korea.
College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea.
J Nat Prod. 2024 Aug 23;87(8):1994-2003. doi: 10.1021/acs.jnatprod.4c00438. Epub 2024 Aug 5.
Soil sustains human life by nourishing crops, storing food sources, and housing microbes, which may affect the nutrition and biosynthesis of secondary metabolites, some of which are used as drugs. To identify lead compounds for a new class of drugs, we collected soil-derived fungal strains from various environments, including urban areas. As various human pathogens are assumed to influence the biosynthetic pathways of metabolites in soil fungi, leading to the production of novel scaffolds, we focused our work on densely populated urban areas and tourist attractions. A soil-derived fungal extract library was screened against MDA-MB-231 cells to derive their cytotoxic activity. Notably, 10 μg/mL of the extract of (DS9-1) was found to exhibit an inhibitory effect of 71%. Fractionation, isolation, and structure elucidation efforts led to the identification of nine new peptaibols, trichoguizaibols A-I (-), comprising 14 amino acid residues (14-AA peptaibols), and three new peptaibols, trichoguizaibols J-L (-), comprising 18 amino acid residues (18-AA peptaibols). The chemical structures of - were determined based on their 1D and 2D NMR spectra, HRESIMS, electronic circular dichroism data, and results of the advanced Marfey's method. The 18-AA peptaibols were found to exhibit cytotoxicity against MDA-MB-231, SK-Hep1, SKOV3, DU145, and HCT116 cells greater than that of the 14-AA peptaibols. Among these compounds, - exhibited potent sub-micromolar IC values. These results are expected to shed light on a new direction for developing novel scaffolds as anticancer agents.
土壤通过滋养作物、储存食物来源和容纳微生物来维持人类生命，而微生物可能会影响次生代谢产物的营养和生物合成，其中一些次生代谢产物可被用作药物。为了鉴定一类新型药物的先导化合物，我们从包括城市地区在内的各种环境中收集了土壤来源的真菌菌株。由于假定各种人类病原体影响土壤真菌中代谢产物的生物合成途径，从而导致新型支架的产生，我们将工作重点放在人口密集的城市地区和旅游景点。对土壤来源的真菌提取物文库针对MDA-MB-231细胞进行筛选，以得出其细胞毒性活性。值得注意的是，发现菌株DS9-1的提取物在浓度为10μg/mL时表现出71%的抑制作用。通过分级分离、分离和结构解析工作，鉴定出了9种新的肽菌素，即曲霉肽菌素A-I（-），它们由14个氨基酸残基组成（14-AA肽菌素），以及3种新的肽菌素，曲霉肽菌素J-L（-），它们由18个氨基酸残基组成（18-AA肽菌素）。化合物-的化学结构是根据它们的一维和二维核磁共振光谱、高分辨电喷雾电离质谱、电子圆二色性数据以及先进的马尔菲方法的结果确定的。发现18-AA肽菌素对MDA-MB-231、SK-Hep1、SKOV3、DU145和HCT116细胞的细胞毒性大于14-AA肽菌素。在这些化合物中，-表现出有效的亚微摩尔IC值。这些结果有望为开发新型抗癌支架药物指明新方向。
