Hexaprenoid hydroquinones, novel inhibitors of the reverse transcriptase of human immunodeficiency virus type 1.
Activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) in the organic extract of the Red Sea sponge Toxiclona toxius was traced by us to five novel natural compounds, namely toxiusol [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 sulfated compounds 1 and 4 yielded the corresponding hydroquinones designated as compounds 2 and 5, and further oxidation of compound 7 afforded the corresponding p-quinone derivative, compound 8. All compounds exhibited 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-dependent DNA polymerase function (with 50% inhibition obtained at 1.5 microM and 95% inhibition at 4.6 microM), whereas the DNA-dependent DNA polymerase was significantly less sensitive to the inhibitor (with 50% inhibition achieved at 6.6 microM and 95% inhibition only at 41.6 microM). The fact that compound 1 discriminates between the two DNA polymerase activities of the RT offers new prospects for developing potent and highly specific anti-RT compounds, since the RNA-dependent DNA polymerase activity of RT is the only unique function that is not expressed at significant levels in uninfected mammalian cells.
Loya
S
S
Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv, Israel.
Tal
R
R
Hizi
A
A
Issacs
S
S
Kashman
Y
Y
Loya
Y
Y
D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification* / Q000494:pharmacology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D006873:Hydroquinones / Q000302:isolation & purification* / Q000494:pharmacology; D008387:Marine Toxins / Q000737:chemistry* / Q000494:pharmacology; D011161:Porifera / Q000737:chemistry*; D018894:Reverse Transcriptase Inhibitors; D013729:Terpenes / Q000302:isolation & purification* / Q000494:pharmacology
D000998:Antiviral Agents; D006873:Hydroquinones; D008387:Marine Toxins; D018894:Reverse Transcriptase Inhibitors; D013729:Terpenes; D054303:HIV Reverse Transcriptase