Garrido-Hernandez Hugo, Moon Kyung D, Geahlen Robert L, Borch Richard F
Department of Medicinal Chemistry and Molecular Pharmacology, and the Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2006 Jun 1;49(11):3368-76. doi: 10.1021/jm060142p.
A novel approach to the intracellular delivery of aryl phosphates has been developed that utilizes a phosphoramidate-based prodrug approach. The prodrugs contain an ester group that undergoes reductive activation intracellularly with concomitant expulsion of a phosphoramidate anion. This anion undergoes intramolecular cyclization and hydrolysis to generate aryl phosphate exclusively with a t(1/2) = approximately 20 min. Phosphoramidate prodrugs (8-10) of phosphate-containing peptidomimetics that target the SH2 domain were synthesized. Evaluation of these peptidomimetic prodrugs in a growth inhibition assay and in a cell-based transcriptional assay demonstrated that the prodrugs had IC50 values in the low micromolar range. Synthesis of phosphorodiamidate analogues containing a P-NH-Ar linker (16-18) was also carried out in the hope that the phosphoramidates released might be phosphatase-resistant. Comparable activation rates and cell-based activities were observed for these prodrugs, but the intermediate phosphoramidate dianion underwent spontaneous hydrolysis with a t(1/2) = approximately 30 min.
已开发出一种利用基于氨基磷酸酯的前药方法向细胞内递送芳基磷酸酯的新方法。这些前药含有一个酯基，该酯基在细胞内进行还原活化，同时排出氨基磷酸酯阴离子。该阴离子进行分子内环化和水解，仅生成芳基磷酸酯，其半衰期（t(1/2)）约为20分钟。合成了靶向SH2结构域的含磷酸肽模拟物的氨基磷酸酯前药（8 - 10）。在生长抑制试验和基于细胞的转录试验中对这些肽模拟物前药进行评估，结果表明这些前药的半数抑制浓度（IC50）值在低微摩尔范围内。还进行了含P-NH-Ar连接基的氨基磷酸二酯类似物（16 - 18）的合成，希望释放出的氨基磷酸酯可能对磷酸酶具有抗性。观察到这些前药具有可比的活化速率和基于细胞的活性，但中间的氨基磷酸二阴离子会发生自发水解，半衰期（t(1/2)）约为30分钟。
