Warnecke André, Fichtner Iduna, Garmann Dirk, Jaehde Ulrich, Kratz Felix
Tumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany, Max-Delbrück Centrum, Robert-Rössle-Strasse 10, 13122 Berlin, Germany.
Bioconjug Chem. 2004 Nov-Dec;15(6):1349-59. doi: 10.1021/bc049829j.
Four platinum (II) complexes (13-16) were synthesized by reacting either Pt trans-DACH(2) with a 6-maleimidocaproic acid, a 15-maleimido-4,7,10,13-tetroxapentadecanoic acid, and a 6-maleimido-4-oxacaproic ester derivative of cyclobutane-1,1-dicarboxylic acid (CDBA) or Pt(NH(3))(2)(2) with a 6-maleimido-4-oxacaproic ester derivative of CBDA. Both complexes containing the 6-maleimido-4-oxacaproic ester (15, 16) showed good water solubility (>/=8 mg/mL) and CE experiments revealed rapid binding to human serum albumin and the formation of biadducts with dGMP and dAMP. In the MaTu xenograft model in nude mice, both complexes showed an improved antitumor effect at their maximum tolerated dose (2 x 50 mg/kg carboplatin equivalents) compared to therapy with carboplatin at equimolar dose or at its optimal dose (2 x 75 mg/kg).
通过使Pt反式-1,2-二氨基环己烷₂与6-马来酰亚胺基己酸、15-马来酰亚胺基-4,7,10,13-四氧杂十五烷酸以及环丁烷-1,1-二羧酸（CDBA）的6-马来酰亚胺基-4-氧杂己酸酯衍生物反应，或者使Pt(NH₃)₂₂与CBDA的6-马来酰亚胺基-4-氧杂己酸酯衍生物反应，合成了四种铂（II）配合物（13 - 16）。两种含有6-马来酰亚胺基-4-氧杂己酸酯的配合物（15、16）表现出良好的水溶性（≥8 mg/mL），毛细管电泳实验表明它们能快速与人血清白蛋白结合，并与dGMP和dAMP形成双加合物。在裸鼠的MaTu异种移植模型中，与等摩尔剂量或最佳剂量（2×75 mg/kg）的卡铂治疗相比，两种配合物在其最大耐受剂量（2×50 mg/kg卡铂当量）下均显示出更好的抗肿瘤效果。
