Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil.
Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos 6627, Campus Pampulha, CEP 31270-901, Belo Horizonte, MG, Brazil; Department of Chemistry, Universidade Federal de Viçosa, CEP 36570-900, Viçosa, MG, Brazil.
Eur J Med Chem. 2019 Apr 15;168:436-446. doi: 10.1016/j.ejmech.2019.02.057. Epub 2019 Feb 25.
In this study, a series of C-28 amides derivatives of hederagenin with or without the presence of an acetyl group at positions 3 and 23 in ring A, were synthetized aiming to develop potent cytotoxic agents. Their structures were confirmed by MS, IR, H NMR and C NMR spectroscopic analyses and their cytotoxic activities were screened in SRB assays using a panel of six human cancer cell lines. The majority of the amide derivatives were cytotoxic for a variety of human tumor cell lines. In general, the hydroxylated derivatives (1a-1d; EC in the range 1.2-22.5 μM) were less active than the acetylated derivatives (2a-2n; EC in the range 0.4-9.0 μM). Hydroxylated derivative bearing pyrrolidinyl substituent 1c, was the most active for HT29 human line cells (EC = 1.2 μM), however their acetylated derivative 2c was the most potent and selective against A2780, FaDu, SW1736 cells, showing EC values between 0.4 and 1.7 μM and SI between 5.6 and 24. Staining experiments combined with fluorescence microscopy indicate that the cell membrane became permeable, and finally a process of secondary necrosis was observed. In addition, the docking results showed that acetylated compounds display more affinity to HER2 than to USP7, indicating that HER2 is a most probable receptor, both proteins found in tumor cell line A2780.
在这项研究中，我们合成了一系列具有或不具有 A 环 3 位和 23 位乙酰基的雪胆苦苷 C-28 酰胺衍生物，旨在开发有效的细胞毒性剂。通过 MS、IR、H NMR 和 C NMR 光谱分析确认了它们的结构，并通过 SRB 测定法筛选了它们对六种人癌细胞系的细胞毒性。大多数酰胺衍生物对多种人肿瘤细胞系具有细胞毒性。一般来说，羟基化衍生物（1a-1d；EC 范围为 1.2-22.5 μM）的活性低于乙酰化衍生物（2a-2n；EC 范围为 0.4-9.0 μM）。具有吡咯烷基取代基的羟基化衍生物 1c 对 HT29 人细胞系最具活性（EC=1.2 μM），但其乙酰化衍生物 2c 对 A2780、FaDu、SW1736 细胞最有效且选择性最强，EC 值在 0.4 和 1.7 μM 之间，SI 值在 5.6 和 24 之间。染色实验结合荧光显微镜观察表明细胞膜变得通透，最后观察到二次坏死的过程。此外，对接结果表明，乙酰化化合物对 HER2 的亲和力高于 USP7，表明 HER2 是 A2780 肿瘤细胞系中最有可能的受体，两种蛋白质都存在于肿瘤细胞系中。
