HEXAPRENOID HYDROQUINONES, NOVEL INHIBITORS OF THE REVERSE-TRANSCRIPTASE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

Activity against human immunodeficiency virus type 1 (HIV-1) reverse t ranscriptase (RT) in the organic extract of the Red Sea sponge Toxiclo na toxius was traced by us to five novel natural compounds, namely tox iusol [1], shaagrockol B [3], shaagrockol C [4], toxicol A [6], all of which are sulfated hexaprenoid hydroquinones, and toxicol B [7], the p-hydroquinone derivative of compound 6. The hydrolysis of the two sul fated compounds 1 and 4 yielded the corresponding hydroquinones design ated as compounds 2 and 5, and further oxidation of compound 7 afforde d the corresponding p-quinone derivative, compound 8. All compounds ex hibited inhibitory activity of both DNA polymerizing functions of HIV- 1 RT but failed to inhibit the RT-associated ribonuclease H activity. Toxiusol [1] was found to be the most potent inhibitor of the RNA-depe ndent DNA polymerase function (with 50% inhibition obtained at 1.5 mu M and 95% inhibition at 4.6 mu M), whereas the DNA-dependent DNA polym erase was significantly less sensitive to the inhibitor (with 50% inhi bition achieved at 6.6 mu M and 95% inhibition only at 41.6 mu M). The face that compound 1 discriminates between the two DNA polymerase act ivities of the RT offers new prospects for developing potent and highl y specific anti-RT compounds, since the RNA-dependent DNA polymerase a ctivity of RT is the only unique function that is not expressed at sig nificant levels in uninfected mammalian cells.