Semisynthesis and Antitumour Evaluation of Natural Derivatives from ent-Kaurene ent-15α-Angeloyloxykaur-l6-en-3β-ol Isolated from Distichoselinum tenuifolium.

IF 5.6 2区 生物学
Yass K Yasser, Daniel Gil, Houda Zentar, María Jesús Durán-Peña, Belen Prados-Lopez, Jorge Juárez-Moreno, José Manuel Botubol-Ares, Ali Haidour, Juan Sainz, Antonio Fernández, Ramón Alvarez-Manzaneda, Rachid Chahboun, Fernando J Reyes-Zurita
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引用次数: 0

Abstract

Two natural ent-kaurene diterpenoids, ent-15α-angeloyloxykaur-16-en-3β-ol (7) and ent-15α-angeloyloxykaur-16-en-3β,9-diol (8), were extracted from the aerial parts of Distichoselinum tenuifolium, and six new derivatives were synthesised from compound (7). The antitumour properties of these natural and derivative ent-kaurenes (2, 7, 9-13) were evaluated in three cancer cell lines: HT29 (colon cancer), HepG2 (hepatocellular carcinoma), and B16-F10 (murine melanoma). Among them, the synthesised ent-kaurene (13) containing an exomethylene-cyclopentanone moiety showed the strongest antiproliferative effects in all cell lines tested, with significantly lower IC50 values around 2.5 μM. Compounds 13 and 12, together with their precursor (7), were selected for further comparative cytometric and microscopic analyses. Cell cycle studies revealed that derivatives 12 and 13 exhibited promising cytostatic activity by inducing selective G2/M phase arrest, particularly effective in HT29 and HepG2 cells. Conversely, precursor (7) showed no significant effect on B16-F10 cell cycle distribution. The Annexin V-FITC/PI double staining assay confirmed the robust apoptotic effects of compounds (7), 12 and 13, with compound 13 inducing up to 99% total apoptosis and exhibiting significant apoptotic activity in all cell lines tested. These apoptotic effects were closely linked to mitochondrial dysfunction, as evidenced by a marked loss of mitochondrial membrane potential and reduced Rh123 fluorescence in treated cells, thereby activating the intrinsic apoptotic pathway. These findings highlight the critical role of mitochondrial disruption in the cytotoxic mechanisms of these ent-kaurenes and underscore their potential as promising anticancer agents.

天竺葵中ent-Kaurene -15α- angeloyloxykaur - 16 -en-3β-ol天然衍生物的半合成及抗肿瘤评价。
从龙参的气相部位提取了2个天然的丁香烯二萜类化合物,ent-15α- angeloyloxykaaur -16-en-3β- 3 -醇(7)和ent-15α- angeloyloxykaaur -16-en-3β,9-二醇(8),并从化合物(7)中合成了6个新的衍生物。对这些天然和衍生的丁香烯(2,7,9 -13)在3种癌细胞系:HT29(结肠癌)、HepG2(肝癌)和B16-F10(小鼠黑色素瘤)中进行了抗肿瘤活性评价。其中,合成的含有外亚甲基环戊酮片段的ent-kaurene(13)在所有细胞系中表现出最强的抗增殖作用,在2.5 μM左右的IC50值显著降低。选择化合物13和12及其前体(7)进行进一步的比较细胞分析和显微镜分析。细胞周期研究表明,衍生物12和13通过诱导选择性G2/M期阻滞表现出良好的细胞抑制活性,对HT29和HepG2细胞特别有效。相反,前体(7)对B16-F10细胞周期分布无显著影响。Annexin V-FITC/PI双染色实验证实了化合物(7)、12和13的强大的凋亡作用,化合物13诱导高达99%的总凋亡,并在所有被测试的细胞系中表现出显著的凋亡活性。这些凋亡效应与线粒体功能障碍密切相关,在处理细胞中线粒体膜电位明显丧失和Rh123荧光降低,从而激活固有的凋亡途径。这些发现强调了线粒体破坏在这些对烯类药物的细胞毒性机制中的关键作用,并强调了它们作为有希望的抗癌药物的潜力。
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来源期刊
自引率
10.70%
发文量
13472
审稿时长
1.7 months
期刊介绍: The International Journal of Molecular Sciences (ISSN 1422-0067) provides an advanced forum for chemistry, molecular physics (chemical physics and physical chemistry) and molecular biology. It publishes research articles, reviews, communications and short notes. Our aim is to encourage scientists to publish their theoretical and experimental results in as much detail as possible. Therefore, there is no restriction on the length of the papers or the number of electronics supplementary files. For articles with computational results, the full experimental details must be provided so that the results can be reproduced. Electronic files regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material (including animated pictures, videos, interactive Excel sheets, software executables and others).
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