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... more
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 mm, 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.
Objectives: This study was done to investigate the role of single nucleotide polymorphisms(SNPs) within genes of phase I (CYP1A1) and phase II (GSTM1, GSTT1,GSTP1) of the xenobiotic metabolism and its association with oral cancer... more
Objectives: This study was done to investigate the role of single nucleotide polymorphisms(SNPs) within genes of phase I (CYP1A1) and phase II (GSTM1, GSTT1,GSTP1) of the xenobiotic metabolism and its association with oral cancer risk.Methods: An unmatched case-control study was conducted using 207 newly diagnosed oral cancer patients and 117 non-cancer subjects selected from the OCRCC database. Peripheral blood was obtained from consented individuals and the CYP1A1, GSTM1, GSTT1 and GSTP1 genotypes were determined using polymerase chain reaction (PCR) and restriction enzyme digestion (RFLP). Simple and multiple logistic regression yielding odds ratio (OR and aOR) were employed to measure the association between genetic polymorphisms and risk of oral cancer. Results: In comparing cases and controls for CYP1A1, GSTM1 and GSTT1 polymorphism, the OR was 0.84 (95 CI 0.534 - 1.330), 0.99 (95 CI 0.627 - 1.554) and 0.87 (95 CI 0.541 - 1.388) respectively. However, the adjusted OR for GSTP1 polymorphism, as compared to the wild-type, was 0.43 (95 CI 0.221 - 0.837). It was noted that polymorphism of GSTP1 conferred a 57 reduction in risk of oral cancer as compared to individuals with the GSTP1 wild type genotype. Meanwhile individuals with combination of betel quid chewing habit and/or GSTP1 polymorphism has 1.6 times the risk of oral cancer although it was not statistically significant (95 CI 0.974 - 2.635). Conclusions: Analysis suggested that polymorphism of GSTP1 seems to have protective effect on the risk of oral cancer
