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Chem Biol Drug Des. 2016 Sep;88(3):460-9. doi: 10.1111/cbdd.12779. Epub 2016 Jun 6.

2-Prenylated m-dimethoxybenzenes as potent inhibitors of 15-lipo-oxygenase: inhibitory mechanism and SAR studies.

Author information

1
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran.
2
Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
3
Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran.
4
Department of Biology, Mashhad Branch, Islamic Azad University, Mashhad, Iran.

Abstract

15-lipo-oxygenases are one of the iron-containing proteins capable of performing peroxidation of unsaturated fatty acids in animals and plants. The critical role of enzymes in the formation of inflammations, sensitivities, and some cancers has been demonstrated in mammals. The importance of enzymes has led to the development of mechanistic studies, product analysis, and synthesis of inhibitors. In this study, a series of allyl and prenyl dimethoxybenzenes were synthesized and their inhibitory potency against soybean 15-Lipo-oxygenase (L1; EC 1,13,11,12) was determined. Among the synthetic compounds, 2,6-dimethoxy-1-isopentenyl-4-methylbenzene, 2,6-dimethoxy-1-geranyl-4-methylbenzene, and 2,6-dimethoxy-1-farnesyl-4-methylbenzene showed the most potent inhibitory activity with IC50 values of 7.6, 5.3, and 0.52 μm, respectively. For some of the compounds, SAR studies showed acceptable relationship between inhibitory potency and enzyme-ligand interactions. Radical scavenging assessment results apart from the SAR studies indicate that electronic properties are the major factors for lipo-oxygenase inhibition potency of the mentioned compounds. Based on the theoretical studies, it was suggested that CH…O intramolecular hydrogen bond between ortho-methoxy oxygen and methine hydrogen atoms is one of the major factors in the stability of 2,6-dimethoxyallyl(or prenyl)benzenes radical via the planarity fixation between phenyl and allyl (or prenyl) pi orbitals.

KEYWORDS:

2,2-diphenylpicrylhydrazyl; density functional theory; docking; hydrogen bond; radical scavenging

PMID:
27113261
DOI:
10.1111/cbdd.12779
[Indexed for MEDLINE]

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