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

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.

A novel class of human 15‐LOX‐1 inhibitors based on 3‐hydroxycoumarin

“…The stabilization energies related to the optimized structures of 3HC to 8HC in both natural and oxy‐radical states were computed using the B3LYP/6‐311++G (d, p) level of theory . An acceptable relationship was only found between the stabilization energy of the radical forms ( E r ) and the DPPH bleaching potencies.…”

Biomimetic Approaches to Synthesis of Cannabidiol

“…Due to the highly stable nature of the benzylic allylic radical 76, as well as the size of the ring, cyclization is slow. Calculations by Sadeghian, Seyedi, and co-workers 63 predict that the C-H bond dissociation energy leading to the m-dimethoxybenzyl allyl radical 76 is about 74 kcal/mol, compared to about 85-90 kcal/mol for typical benzylic radicals, and about 98 kcal/mol for t-butyl radicals 64,65 . They have suggested that intramolecular CH-O interactions are involved in stabilizing the planar conformation of the radical.…”