Organic Chemistry Laboratory, University of Bayreuth, Universitaetsstrasse 30, 95440 Bayreuth, Germany.
Eur J Med Chem. 2010 May;45(5):1972-5. doi: 10.1016/j.ejmech.2010.01.040. Epub 2010 Jan 28.
Ru(eta6-arene) complexes of epidermal growth factor receptor (EGFR) inhibiting tyrphostins 1a and 1b were prepared, characterized and tested for DNA interaction and bioactivity in four human tumor cell lines. The intrinsic cytotoxicity and cell line selectivity of o-hydroxyanisol 1a was greatly enhanced in its Ru(eta6-p-cymene) complex 2a and in its Ru(eta6-toluene) complex 3a. Complex 2a was particularly efficacious against multi-drug resistant EGFR(+) MCF-7/Topo breast carcinoma cells and also against mTOR-dependent EGFR(-) HL-60 leukemia cells. Complex 3a showed enhanced activity only against 518A2 melanoma cells and HL-60 cells, which are both known to express the mTOR protein. DNA was strongly metallated (ca. 1.7-2%) by all new Ru complexes without undergoing topological changes. Apparently, by complexation to Ru fragments tyrphostin derivatives can address additional biological targets in a manner instrumental to antitumoral strategies.
制备了表皮生长因子受体 (EGFR) 抑制性 tyrphostin 1a 和 1b 的 Ru(eta6-芳烃)配合物，并对其进行了表征，研究了它们在四种人肿瘤细胞系中的 DNA 相互作用和生物活性。邻羟基茴香醚 1a 在其 Ru(eta6-对甲基苯)配合物 2a 和 Ru(eta6-甲苯)配合物 3a 中的固有细胞毒性和细胞系选择性得到了极大提高。配合物 2a 对多药耐药性 EGFR(+) MCF-7/Topo 乳腺癌细胞和 mTOR 依赖性 EGFR(-)HL-60 白血病细胞也特别有效。配合物 3a 仅对 518A2 黑色素瘤细胞和 HL-60 细胞表现出增强的活性，这两种细胞都已知表达 mTOR 蛋白。所有新的 Ru 配合物都强烈地使 DNA 金属化（约 1.7-2%），而不会发生拓扑变化。显然，通过与 Ru 片段的络合，tyrophostin 衍生物可以以有助于抗肿瘤策略的方式针对其他生物靶标。
