Alberta Ingenuity Centre for Carbohydrate Science and Department of Chemistry, The University of Alberta, Edmonton, Alberta, Canada.
Bioorg Med Chem. 2011 Mar 1;19(5):1779-89. doi: 10.1016/j.bmc.2011.01.014. Epub 2011 Jan 14.
In earlier investigations we have described the synthesis and biological evaluation of a panel of novel glycosylated heteroaromatics (1-12). It was found that these compounds can bind to DNA in vitro and are cytotoxic against several cancer cell lines at low micromolar concentration. We report here structure-activity studies of these molecules with respect to DNA binding and cytotoxicity. In particular the structure of the linker moiety between the carbohydrate and the intercalator, the stereochemistry at the anomeric position, and the substituents and stereochemistry at C-4 in one of the carbohydrate residues (4-amino-2,3,4,6-tetradeoxy-α-L-threo-hexopyranose) are investigated. All these structural features were identified to have a clear influence on DNA binding; however, only the substituents at C-4 in the carbohydrate residue exhibited an obvious impact on cytotoxicity. It was found that the amino group at C-4 was favored over all other substituents with regard to both DNA binding and cytotoxicity. The information gathered from these structure-activity investigations suggested that future work on the preparation of additional analogues should focus on molecules containing an amino sugar moiety.
在早期的研究中，我们描述了一组新型糖基杂芳烃（1-12）的合成和生物学评价。结果发现，这些化合物可以在体外与 DNA 结合，并在低微摩尔浓度下对几种癌细胞系具有细胞毒性。我们在这里报告了这些分子的构效关系研究，包括与 DNA 结合和细胞毒性。特别是糖和嵌入剂之间连接部分的结构、在糖的端基碳原子的立体化学、以及一个糖残基（4-氨基-2,3,4,6-四脱氧-α-L-苏阿洛己吡喃糖）上取代基和立体化学的结构。所有这些结构特征都被确定对 DNA 结合有明显的影响；然而，只有糖残基中 C-4 上的取代基对细胞毒性有明显的影响。结果发现，C-4 上的氨基取代基在 DNA 结合和细胞毒性方面都优于其他取代基。从这些构效关系研究中收集到的信息表明，未来在制备其他类似物的工作中应重点关注含有氨基糖部分的分子。
