前列腺特异性膜抗原的受限氨基磷酸酯抑制剂的合成与评价
Synthesis and evaluation of constrained phosphoramidate inhibitors of prostate-specific membrane antigen.
作者信息
Ley Corinne R, Beattie Nathan R, Dannoon Shorouk, Regan Melanie, VanBrocklin Henry, Berkman Clifford E
机构信息
Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.
出版信息
Bioorg Med Chem Lett. 2015 Jun 15;25(12):2536-9. doi: 10.1016/j.bmcl.2015.04.047. Epub 2015 Apr 29.
Prostate-specific membrane antigen (PSMA) is a cell-surface enzyme-biomarker that is actively pursued for targeted delivery of imaging and therapeutic agents for prostate cancer. Our lab has developed PSMA inhibitors based on a phosphoramidate scaffold, which has shown both high selectivity for PSMA-positive tumors and rapid clearance in vivo when radiolabeled with (18)F. However, this scaffold exhibits hydrolytic instability under low pH and high temperature conditions, barring the use of other imaging or therapeutic radionuclides such as (68)Ga or (177)Lu. Previous studies in our lab have shown a trend in increasing acid stability as the distance between the phosphoramidate core and the α-carboxylate of the P1 residue is increased. Therefore, a new generation of phosphoramidate inhibitors was developed based on trans-4-hydroxyproline as the P1 residue to restrict the interaction of the α-carboxylate to the phosphoramidate core. These hydroxyproline inhibitors demonstrated comparable IC50 values to earlier generations as well as enhanced thermal and acid stability.
前列腺特异性膜抗原（PSMA）是一种细胞表面酶生物标志物，目前正积极探索将其用于前列腺癌成像和治疗药物的靶向递送。我们实验室基于氨基磷酸酯支架开发了PSMA抑制剂，该抑制剂对PSMA阳性肿瘤显示出高选择性，并且在用（18）F进行放射性标记时在体内具有快速清除率。然而，这种支架在低pH和高温条件下表现出水解不稳定性，阻碍了使用其他成像或治疗放射性核素，如（68）Ga或（177）Lu。我们实验室之前的研究表明，随着氨基磷酸酯核心与P1残基的α-羧酸盐之间距离的增加，酸稳定性呈增加趋势。因此，基于反式-4-羟基脯氨酸作为P1残基开发了新一代氨基磷酸酯抑制剂，以限制α-羧酸盐与氨基磷酸酯核心的相互作用。这些羟基脯氨酸抑制剂表现出与早期几代相当的IC50值以及增强后的热稳定性和酸稳定性。
Zotero 插件