Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo
| Autor: | Shuping Dong, Yolanda Sanchez, Tindy Li, Claudia E. Murar, Anthony J. Wilson, Brent W. Mccleland, Hongwei Qi, Patricia L. Podolin, Marc Galop, Christopher J. Moody, Hongxing Yan, John Yonchuk, Roderick S. Davis, Alan P. Graves, Catherine Booth-Genthe, Joseph P. Foley, Jen-Pyng Kou, Jeffrey K. Kerns, Brian Bolognese, James F. Callahan, Mary Mentzer, Lawrence Wolfe, Jeffrey C. Boehm, Robin Carr |
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| Rok vydání: | 2019 |
| Předmět: |
Antioxidant
NF-E2-Related Factor 2 medicine.medical_treatment Clinical Biochemistry Gene Expression Pharmaceutical Science medicine.disease_cause Biochemistry Antioxidants Cell Line Structure-Activity Relationship chemistry.chemical_compound Isothiocyanates Thiocarbamates In vivo Drug Discovery medicine Animals Humans Thermal stability Molecular Biology Kelch-Like ECH-Associated Protein 1 Natural product Molecular Structure Organic Chemistry KEAP1 Rats Mice Inbred C57BL Oxidative Stress Solubility chemistry Sulfoxides Isothiocyanate Biophysics Molecular Medicine Cyclobutanes Heme Oxygenase-1 Oxidative stress Signal Transduction Sulforaphane |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:579-588 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2018.12.026 |
| Popis: | The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress. |
| Databáze: | OpenAIRE |
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