Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128 Palermo, Italy.
NBFC-National Biodiversity Future Center, Piazza Marina 60, 90133 Palermo, Italy.
Int J Mol Sci. 2024 Mar 31;25(7):3925. doi: 10.3390/ijms25073925.
The antitumor activity of different -kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19-di-oxo analogues obtained from atractyligenin by modifying the C-2, C-15, and C-19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10-300 μM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di-oxidized compounds were more effective than their alcoholic precursors. The di-oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco-2) at 24 h when used at low doses (2.5-15 μM), while they turned out to be poorly effective in differentiated Caco-2 cells, a model of polarized enterocytes. The data reported here provide evidence that di-oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase-3 and fragmentation of its target PARP-1.
不同的贝壳杉烷二萜的抗肿瘤活性已得到广泛研究。几项研究表明，贝壳杉烯二萜的合成衍生物具有优异的抗肿瘤活性。在这项研究中，通过修饰 C-2、C-15 和 C-19 位，设计了一系列新的合成酰胺及其 15,19-二酮类似物，以获得一组具有不同酰胺氮取代的衍生物。用不同浓度的所得化合物（10-300 μM）处理 48 h 后，观察到 HCT116 结肠癌细胞活力降低。所有二氧化化合物都比其醇前体更有效。二氧化化合物在低剂量（2.5-15 μM）时已经降低了两种结肠癌细胞（HCT116 和 Caco-2）的活力，而在分化的 Caco-2 细胞（极化肠细胞的模型）中效果较差。这里报道的数据提供了证据，证明二氧化化合物诱导了细胞凋亡死亡，如处理细胞中出现浓缩和碎片化的 DNA 以及 caspase-3 的激活和其靶蛋白 PARP-1 的片段化所证明的那样。
