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SAR of L-ABBA analogs for GGT1 inhibitory activity and L-ABBA's effect on plasma cysteine and GSH species.
Bist, Ganesh; Luong, Nguyen T; Mahabubur Rahman, Kazi Md; Ruszaj, Donna M; Li, Chenglong; Hanigan, Marie H; You, Youngjae.
Afiliación
  • Bist G; Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States.
  • Luong NT; Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States.
  • Mahabubur Rahman KM; Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States.
  • Ruszaj DM; Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States.
  • Li C; Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, United States.
  • Hanigan MH; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States.
  • You Y; Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY 14214, United States. Electronic address: yjyou@buffalo.edu.
Bioorg Med Chem Lett ; 92: 129406, 2023 Aug 15.
Article en En | MEDLINE | ID: mdl-37423504
Gamma-glutamyl transferase 1 (GGT1) is a critical enzyme involved in the hydrolysis and/or transfer of gamma-glutamyl groups of glutathione, which helps maintain cysteine levels in plasma. In this study, we synthesized L-ABBA analogs to investigate their inhibitory effect on GGT1 hydrolysis and transpeptidase activity, with the goal of defining the pharmacophore of L-ABBA. Our structure-activity relationship (SAR) study revealed that an α-COO- and α-NH3+ group, as well as a two-CH2 unit distance between α-C and boronic acid, are essential for the activity. The addition of an R (alkyl) group at the α-C reduced the activity of GGT1 inhibition, with L-ABBA being the most potent inhibitor among the analogs. Next, we investigated the impact of L-ABBA on plasma levels of cysteine and GSH species, with the expectation of observing reduced cysteine levels and enhanced GSH levels due to its GGT1 inhibition. We administered L-ABBA intraperitoneally and determined the plasma levels of cysteine, cystine, GSH, and GSSG using LCMS. Our results showed time- and dose-dependent L-ABBA changes in total plasma cysteine and GSH levels. This study is the first to demonstrate the regulation of plasma thiol species upon GGT1 inhibition, with plasma cystine levels reduced by up to âˆ¼ 75 % with L-ABBA (0.3 mg/dose). Cancer cells are highly dependent on the uptake of cysteine from plasma for maintaining high levels of intracellular glutathione. Thus, our findings suggest that GGT1 inhibitors, such as L-ABBA, have the potential to be used in GSH reduction thereby inducing oxidative stress in cancer cells and reducing their resistance to many chemotherapeutic agents.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido