Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Eur J Med Chem. 2017 Oct 20;139:325-336. doi: 10.1016/j.ejmech.2017.07.048. Epub 2017 Jul 26.
Substantial progress has been described in the study of puromycin and its analogs for antibiotic properties. However, the peptidase inhibitory activity of related analogs has not been explored as extensively. Specifically, inhibiting aminopeptidases for achieving antitumor effect has been sparsely investigated. Herein, we address this challenge by reporting the synthesis of a series of analogs based on the structural template of puromycin. We also present exhaustive biochemical and in vitro analyses in support of our thesis. Analyzing the structure-activity relationship revealed a steric requirement for maximum potency. Effective inhibitors of Puromycin-Sensitive Aminopeptidase (PSA) are disclosed here. These potential therapeutic agents display superior in vitro antitumor potency against two leukemic cell lines, as compared to known inhibitors of aminopeptidases.
在研究嘌呤霉素及其类似物的抗生素特性方面已经取得了很大的进展。然而，相关类似物的肽酶抑制活性并没有被广泛探索。具体来说，通过抑制氨肽酶来实现抗肿瘤作用的研究还很少。在这里，我们通过报道一系列基于嘌呤霉素结构模板的类似物的合成来解决这一挑战。我们还提供了详尽的生化和体外分析来支持我们的论文。通过分析构效关系，我们发现了达到最大活性的空间要求。本文揭示了嘌呤霉素敏感氨肽酶（PSA）的有效抑制剂。与已知的氨肽酶抑制剂相比，这些潜在的治疗剂对两种白血病细胞系的体外抗肿瘤活性更强。
