Animati Fabio, Berettoni Marco, Bigioni Mario, Binaschi Monica, Felicetti Patrizia, Gontrani Lorenzo, Incani Ottaviano, Madami Andrea, Monteagudo Edith, Olivieri Lauso, Resta Stefano, Rossi Cristina, Cipollone Amalia
Chemistry Department, Menarini Ricerche S.p.A. via Tito Speri 10, 00040 Pomezia Roma, Italy.
ChemMedChem. 2008 Feb;3(2):266-79. doi: 10.1002/cmdc.200700232.
A new series of indolocarbazole glycosides containing disaccharides were synthesized and their in vitro antiproliferative activity was evaluated against three human cancer cell lines (A2780, H460, and GLC4). Cytotoxicity appeared to be remarkably affected by the regio- and stereochemical features of the disaccharide moiety. In vivo antitumor activity of the compounds studied, two of which having IC(50)<100 nm, was determined using ovarian cancer cell line A2780 xenografted on nude mice. One compound showed an efficacy similar to that of the reference compound edotecarin, though with a lower long-lasting activity. The topoisomerase I inhibitory properties of some compounds were also examined. Molecular dynamics simulations of the ternary topoisomerase I-DNA-ligand complexes were performed to analyze the structural features of topoisomerase I poisoning with this class of indolocarbazoles. A plausible explanation of their biological behavior was provided. These theoretical results were compared with the recently published crystal structure of an indolocarbazole monosaccharide bound to the covalent human topoisomerase I-DNA complex.
合成了一系列新的含二糖的吲哚咔唑糖苷，并评估了它们对三种人类癌细胞系（A2780、H460和GLC4）的体外抗增殖活性。细胞毒性似乎受到二糖部分的区域和立体化学特征的显著影响。使用接种在裸鼠上的卵巢癌细胞系A2780测定了所研究化合物的体内抗肿瘤活性，其中两种化合物的IC(50)<100 nm。一种化合物显示出与参考化合物依多卡琳相似的疗效，尽管其持久活性较低。还研究了一些化合物的拓扑异构酶I抑制特性。进行了三元拓扑异构酶I-DNA-配体复合物的分子动力学模拟，以分析这类吲哚咔唑使拓扑异构酶I中毒的结构特征。对它们的生物学行为提供了一个合理的解释。将这些理论结果与最近发表的与共价人拓扑异构酶I-DNA复合物结合的吲哚咔唑单糖的晶体结构进行了比较。
