Synthesis and Biological Evaluation of 2-Substituted-5-(4-nitrophenylsulfonamido)benzoxazoles as Human GST P1-1 Inhibitors, and Description of the Binding Site Features

• Published in: ChemMedChem 2014-05, Vol.9 (5), p.984-992
• Main Authors: Ertan-Bolelli, Tuğba, Musdal, Yaman, Bolelli, Kayhan, Yilmaz, Serap, Aksoy, Yasemin, Yildiz, Ilkay, Aki-Yalcin, Esin, Yalcin, Ismail
• Format: Article
• Language: English
• Subjects: benzoxazoles; Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Binding Sites - drug effects; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; glutathione; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - metabolism; glutathione-S-transferase; Humans; Models, Molecular; molecular modeling; Molecular Structure; Structure-Activity Relationship; sulfonamides
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201400010

Glutathione‐S‐transferases (GSTs) are enzymes involved in cellular detoxification by catalyzing the nucleophilic attack of glutathione (GSH) on the electrophilic center of numerous of toxic compounds and xenobiotics, including chemotherapeutic drugs. Human GST P1‐1, which is known as the most prevalent isoform of the mammalian cytosolic GSTs, is overexpressed in many cancers and contributes to multidrug resistance by directly conjugating to chemotherapeutics. It is suggested that this resistance is related to the high expression of GST P1‐1 in cancers, thereby contributing to resistance to chemotherapy. In addition, GSTs exhibit sulfonamidase activity, thereby catalyzing the GSH‐mediated hydrolysis of sulfonamide bonds. Such reactions are of interest as potential tumor‐directed prodrug activation strategies. Herein we report the design and synthesis of some novel sulfonamide‐containing benzoxazoles, which are able to inhibit human GST P1‐1. Among the tested compounds, 2‐(4‐chlorobenzyl)‐5‐(4‐nitrophenylsulfonamido)benzoxazole (5 f) was found as the most active hGST P1‐1 inhibitor, with an IC50 value of 10.2 μM, showing potency similar to that of the reference drug ethacrynic acid. Molecular docking studies performed with CDocker revealed that the newly synthesized 2‐substituted‐5‐(4‐nitrophenylsulfonamido)benzoxazoles act as catalytic inhibitors of hGST P1‐1 by binding to the H‐site and generating conjugates with GSH to form S‐(4‐nitrophenyl)GSH (GS–BN complex) via nucleophilic aromatic substitution reaction. The 4‐nitrobenzenesulfonamido moiety at position 5 of the benzoxazole ring is essential for binding to the H‐site and for the formation of the GST‐mediated GSH conjugate. Irresistible conjugates: We report the synthesis of some novel sulfonamido‐containing benzoxazoles. Among the tested compounds, 5 f was found to be the most active hGST P1‐1 inhibitor, showing similar potency to that of the reference agent, ethacrynic acid. Molecular docking studies revealed that the synthesized sulfonamido‐containing benzoxazoles act as inhibitors of hGST P1‐1 by binding to the H‐site and forming conjugates with GSH via nucleophilic aromatic substitution.