Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo. Issue 4 (15th February 2019)

• Record Type: Journal Article
• Authors: Boehm, Jeffrey; Davis, Roderick; Murar, Claudia E.; Li, Tindy; McCleland, Brent; Dong, Shuping; Yan, Hongxing; Kerns, Jeffrey; Moody, Christopher J.; Wilson, Anthony J.; Graves, Alan P.; Mentzer, Mary; Qi, Hongwei; Yonchuk, John; Kou, Jen-Pyng; Foley, Joseph; Sanchez, Yolanda; Podolin, Patricia L.; Bolognese, Brian; Booth-Genthe, Catherine; Galop, Marc; Wolfe, Lawrence; Carr, Robin; Callahan, James F.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 4(2019)
• Page Start: 579
• Page End: 588
• Publication Date: 2019-02-15
• Subjects: SFN sulforaphane -- KEAP1 Kelch-like ECH-associated protein 1 -- GSH glutathione -- NAC N-acetyl cysteine -- NHBE normal human bronchial epithelial cells -- NQO1 NAD(P)-H:quinone acceptor oxidoreductase 1 -- Nrf2 nuclear factor erythroid 2-related factor 2 -- BEAS2B bronchial epithelium + adenovirus 12-SV40 virus hybrid (Ad12SV40), an immortalized human bronchial epithelial cell line -- COPD chronic obstructive pulmonary disease; Nrf2 -- KEAP1 -- Sulforaphane -- Isothiocyanate -- COPD; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.12.026
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.