Parker Erica N, Odutola Samuel O, Wang Yifan, Strecker Tracy E, Mukherjee Rajeswari, Shi Zhe, Chaplin David J, Trawick Mary Lynn, Pinney Kevin G
Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States.
Institute of Biomedical Studies, Baylor University, One Bear Place #97224, Waco, TX 76798-7224, United States.
Bioorg Med Chem Lett. 2017 Mar 1;27(5):1304-1310. doi: 10.1016/j.bmcl.2016.12.039. Epub 2016 Dec 21.
The magnitude of expression of cathepsin L, often upregulated in the tumor microenvironment, correlates with the invasive and metastatic nature of certain tumors. Inhibition of cathepsin L represents an emerging strategy for the treatment of metastatic cancer. A potent, small-molecule inhibitor (referred to as KGP94) of cathepsin L, and new KGP94 analogues were synthesized. (3,5-Dibromophenyl)-(3-hydroxyphenyl) ketone thiosemicarbazone (22), with an IC value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC=189nM). Due to limited aqueous solubility of KGP94, a water-soluble phosphate salt (KGP420) was prepared in order to facilitate future in vivo studies. Enzymatic hydrolysis with alkaline phosphatase (ALP) demonstrated that the phosphate prodrug, KGP420, was readily converted to the parent compound, KGP94.
组织蛋白酶L的表达量在肿瘤微环境中常常上调，它与某些肿瘤的侵袭和转移特性相关。抑制组织蛋白酶L是一种新兴的治疗转移性癌症的策略。合成了一种强效的组织蛋白酶L小分子抑制剂（称为KGP94）以及新的KGP94类似物。(3,5-二溴苯基)-(3-羟基苯基)酮硫代半卡巴腙（22）的IC值为202nM，与KGP94（IC = 189nM）相比，对组织蛋白酶L表现出相似的抑制活性。由于KGP94的水溶性有限，制备了一种水溶性磷酸盐（KGP420）以促进未来的体内研究。用碱性磷酸酶（ALP）进行酶促水解表明，磷酸盐前药KGP420很容易转化为母体化合物KGP94。
