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Antiviral Activities of Methylated Nordihydroguaiaretic Acids. 1. Synthesis, Structure Identification, and Inhibition of Tat-Regulated HIV Transactivation

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Organosilicon and Synthesis Laboratory, Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30043, Republic of China, Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529, Republic of China, and Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218
Cite this: J. Med. Chem. 1998, 41, 16, 2994–3000
Publication Date (Web):July 11, 1998
https://doi.org/10.1021/jm970819w
Copyright © 1998 American Chemical Society

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    Abstract

    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-O-methylated 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 (26 and 810), tetra-O-methyl-NDGA (10) showed the strongest anti-HIV activity (IC50 11 μM). Chemically synthesized 3‘-O-methyl-NDGA ((±)-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.

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     National Tsing Hua University.

     Academia Sinica.

    §

     The Johns Hopkins University.

    *

     Corresponding author. Tel:  410-516-5181. Fax:  410-516-5213. E-mail:  [email protected]. Direct correspondence concerning chemical synthesis to J. R. Hwu.

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    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    MENDELEY PAIRING EXPIRED
    Your Mendeley pairing has expired. Please reconnect