ANTIVIRAL ACTIVITIES OF METHYLATED NORDIHYDROGUAIARETIC ACIDS - 1 - SYNTHESIS, STRUCTURE IDENTIFICATION, AND INHIBITION OF TAT-REGULATED HIV TRANSACTIVATION

Nordihydroguaiaretic acid (NDGA, meso-1) possesses four phenolic hydro xyl 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 degrees C ga ve nine methylated products. Eight of those mono-, di-, tri-, and tetr a-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 NDG A by use of 4.1 equiv of dimethyl sulfate for the methylation. Among t he eight different methylated NDGAs (2-6 and 8-10), tetra-O-methyl-NDG A (10) showed the strongest anti-HIV activity (IC50 11 mu M). Chemical ly synthesized 3'-O-methyl-NDGA ((+/-)-2) showed identical anti-HIV ac tivity (IC50 25 mu M) to the lignan isolated from Creosote Bush. Ligna ns with methylated catecholic hydroxyl groups can be produced in large quantities with low cost. At drug concentrations below 30 mu M, tetra methyl NDGA (10) was a stronger anti-HIV agent than mono- and dimethyl ated NDGAs.