University of Chemistry and Technology, Department of Chemistry of Natural Compounds, Technická 5, 166 28 Prague 6, Czech Republic; Institute of Experimental Botany AS CR, v.v.i., Isotope Laboratory, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
Palacký University, Centre of the Region Haná for Biotechnological and Agricultural Research, Department of Chemical Biology and Genetics, Šlechtitelů 27, 783 71 Olomouc, Czech Republic.
Eur J Med Chem. 2018 Feb 10;145:41-50. doi: 10.1016/j.ejmech.2017.12.096. Epub 2018 Jan 4.
A series of picolyl amides of betulinic acid (3a-3c and 6a-6c) was prepared and subjected to the cytotoxicity screening tests. Structure-activity relationships studies resulted in finding differences in biological activity in dependence on o-, m- and p-substitution of the pyridine ring in the target amides, when cytotoxicity data of 3a-3c and 6a-6c were obtained and compared. The amides 3b and 3a displayed cytotoxicity (given in the IC values) in G-361 (0.5 ± 0.1 μM and 2.4 ± 0.0 μM, respectively), MCF7 (1.4 ± 0.1 μM and 2.2 ± 0.2 μM, respectively), HeLa (2.4 ± 0.4 μM and 2.3 ± 0.5 μM, respectively) and CEM (6.5 ± 1.5 μM and 6.9 ± 0.4 μM, respectively) tumor cell lines, and showed weak effect in the normal human fibroblasts (BJ). Selectivity against all tested cancer cells was determined and compared to normal cells with therapeutic index (TI) between 7 and 100 for compounds 3a and 3b. The therapeutic index (TI = 100) was calculated for human malignant melanoma cell line (G-361) versus normal human fibroblasts (BJ). The cytotoxicity of other target amides (3c and 6a-6c) revealed lower effects than 3a and 3b in the tested cancer cell lines.
一系列桦木酸的皮考啉酰胺（3a-3c 和 6a-6c）被制备并进行了细胞毒性筛选测试。构效关系研究结果表明，当获得和比较 3a-3c 和 6a-6c 的细胞毒性数据时，目标酰胺中吡啶环的邻位、间位和对位取代会导致生物活性的差异。酰胺 3b 和 3a 在 G-361（分别为 0.5±0.1 μM 和 2.4±0.0 μM）、MCF7（分别为 1.4±0.1 μM 和 2.2±0.2 μM）、HeLa（分别为 2.4±0.4 μM 和 2.3±0.5 μM）和 CEM（分别为 6.5±1.5 μM 和 6.9±0.4 μM）肿瘤细胞系中显示出细胞毒性（以 IC 值表示），并且在正常人类成纤维细胞（BJ）中显示出较弱的作用。测定了对所有测试的癌细胞的选择性，并与化合物 3a 和 3b 的治疗指数（TI）在 7 到 100 之间的正常细胞进行了比较。对于人类恶性黑色素瘤细胞系（G-361）与正常人类成纤维细胞（BJ），计算了治疗指数（TI=100）。其他目标酰胺（3c 和 6a-6c）的细胞毒性在测试的癌细胞系中显示出比 3a 和 3b 更低的作用。
