Discovery of a crystalline sulforaphane analog with good solid-state stability and engagement of the Nrf2 pathway in vitro and in vivo.
Animals
Antioxidants
/ chemical synthesis
Cell Line
Cyclobutanes
/ chemical synthesis
Drug Discovery
Gene Expression
Heme Oxygenase-1
/ genetics
Humans
Isothiocyanates
/ chemical synthesis
Kelch-Like ECH-Associated Protein 1
/ metabolism
Mice, Inbred C57BL
Molecular Structure
NF-E2-Related Factor 2
/ metabolism
Oxidative Stress
/ drug effects
Rats
Signal Transduction
/ drug effects
Solubility
Structure-Activity Relationship
Sulfoxides
Thiocarbamates
/ chemical synthesis
COPD
Isothiocyanate
KEAP1
Nrf2
Sulforaphane
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 02 2019
15 02 2019
Historique:
received:
18
09
2018
revised:
06
12
2018
accepted:
15
12
2018
pubmed:
11
1
2019
medline:
15
1
2020
entrez:
11
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30626555
pii: S0968-0896(18)31630-4
doi: 10.1016/j.bmc.2018.12.026
pii:
doi:
Substances chimiques
Antioxidants
0
Cyclobutanes
0
Isothiocyanates
0
KEAP1 protein, human
0
Kelch-Like ECH-Associated Protein 1
0
NF-E2-Related Factor 2
0
NFE2L2 protein, human
0
Sulfoxides
0
Thiocarbamates
0
HMOX1 protein, human
EC 1.14.14.18
Heme Oxygenase-1
EC 1.14.14.18
sulforaphane
GA49J4310U
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
579-588Informations de copyright
Copyright © 2018. Published by Elsevier Ltd.