36469-60-0Relevant articles and documents
Ring substitution influences oxidative cyclisation and reactive metabolite formation of nordihydroguaiaretic acid analogues
Asiamah, Isaac,Hodgson, Heather L.,Maloney, Katherine,Allen, Kevin J.H.,Krol, Ed S.
supporting information, p. 7007 - 7014 (2015/11/11)
Nordihydroguaiaretic acid (NDGA) is a natural polyphenol with a broad spectrum of pharmacological properties. However, its usefulness is hindered by the lack of understanding of its pharmacological and toxicological pathways. Previously we showed that oxidative cyclisation of NDGA at physiological pH forms a dibenzocyclooctadiene that may have therapeutic benefits whilst oxidation to an ortho-quinone likely mediates toxicological properties. NDGA analogues with higher propensity to cyclise under physiologically relevant conditions might have pharmacological implications, which motivated this study. We synthesized a series of NDGA analogues which were designed to investigate the structural features which influence the intramolecular cyclisation process and help to understand the mechanism of NDGA's autoxidative conversion to a dibenzocyclooctadiene lignan. We determined the ability of the NDGA analogues investigated to form dibenzocyclooctadienes and evaluated the oxidative stability at pH 7.4 of the analogues and the stability of any dibenzocyclooctadienes formed from the NDGA analogues. We found among our group of analogues the catechols were less stable than phenols, a single catechol-substituted ring is insufficient to form a dibenzocyclooctadiene lignan, and only compounds possessing a di-catechol could form dibenzocyclooctadienes. This suggests that quinone formation may not be necessary for cyclisation to occur and the intramolecular cyclisation likely involves a radical-mediated rather than an electrophilic substitution process. We also determined that the catechol dibenzocyclooctadienes autoxidised at comparable rates to the parent catechol. This suggests that assigning in vitro biological activity to the NDGA dibenzocyclooctadiene is premature and requires additional study.
An efficient method for the synthesis of lignans
Wang, Qian,Yang, Yong,Li, Ying,Yu, Wei,Hou, Zi Jie
, p. 6107 - 6112 (2007/10/03)
An efficient approach for the synthesis of several types of lignans (dibenzylbutanediols, dibenzylbutanes, substituted tetrahydrofurans, aryldihydronaphthalenes, arylnaphthalenes, and aryltetralins) was developed. The regioselective oxidative coupling of ethyl ferulate was used as the key step.
Antiviral activities of methylated nordihydroguaiaretic acids. 1. Synthesis, structure identification, and inhibition of Tat-regulated HIV transactivation
Hwu, Jih Ru,Tseng, Wen Nan,Gnabre, John,Giza, Paul,Huang, Ru Chih C.
, p. 2994 - 3000 (2007/10/03)
Nordihydroguaiaretic acid (NDGA, meso-1) possesses four phenolic hydroxyl groups. Treatment of NDGA with 0.50-4.1 equiv of dimethyl sulfate and 3.0-6.0 equiv of potassium carbonate in acetone at 56 °C gave nine methylated products. Eight of those mono-, di-, tri-, and tetra-Omethylated NDGAs were isolated in pure form, and their structures were identified unambiguously by spectroscopic methods. A preparative amount of tetramethyl NDGA M4N (10) was obtained in 99% yield from NDGA by use of 4.1 equiv of dimethyl sulfate for the methylation. Among the eight different methylated NDGAs (2-6 and 8-10), tetra-O-methyl-NDGA (10) showed the strongest anti-HIV activity (IC50 11 μM). Chemically synthesized 3'-O-methylNDGA ((±)-2) showed identical anti-HIV activity (IC50 25 μM) to the lignan isolated from Creosote Bush. Lignans with methylated catecholic hydroxyl groups can be produced in large quantities with low cost. At drug concentrations below 30 μM, tetramethyl NDGA (10) was a stronger anti-HIV agent than mono- and dimethylated NDGAs.
