Synthesis and biological evaluation of a water-soluble phosphate prodrug salt and structural analogues of KGP94, a lead inhibitor of cathepsin L.

Autor: Parker EN; Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States., Odutola SO; Institute of Biomedical Studies, Baylor University, One Bear Place #97224, Waco, TX 76798-7224, United States., Wang Y; Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States., Strecker TE; Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States., Mukherjee R; Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States., Shi Z; Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States., Chaplin DJ; Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, TX 76798-7348, United States; Mateon Therapeutics, Inc., 701 Gateway Blvd, Suite 210, South San Francisco, CA 94080, United States., Trawick ML; 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; Mateon Therapeutics, Inc., 701 Gateway Blvd, Suite 210, South San Francisco, CA 94080, United States. Electronic address: Mary_Lynn_Trawick@baylor.edu., Pinney KG; 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; Mateon Therapeutics, Inc., 701 Gateway Blvd, Suite 210, South San Francisco, CA 94080, United States. Electronic address: Kevin_Pinney@baylor.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Mar 01; Vol. 27 (5), pp. 1304-1310. Date of Electronic Publication: 2016 Dec 21.
DOI: 10.1016/j.bmcl.2016.12.039
Abstrakt: 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 50 value of 202nM, exhibited similar inhibitory activity against cathepsin L compared to KGP94 (IC 50 =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.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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