AIDS Res Hum Retroviruses. 1997 May 20;13(8):695-705. Unique Identifier
Anti-HIV-1 activity of tetrahydronaphthalene (THN) derivatives of lignan
compounds was studied. THN derivatives prevented cell death caused by
HIV-1 infection in MT-4 cells. They also inhibited giant cell formation
by HIV-1 in Sup-T1 cells, and p24 production in HIV-1-infected H9 cells.
The 50% effective concentration (ED50) of the most active compound, 1737
aphtho[2,3-c]thiophene], for inhibition of the cytopathic effects of
HIV-1 infection ranged from 0.15 to 0.8 microM. The 50% cytotoxic
concentration (CC50) of compound 1737 measured by the viability of MT-4
cells was 58 microM, indicating a selective index (CC50/ED50) of 70-400.
Substitution of the phenyl ring with other structures markedly decreased
cytotoxicity but did not affect the antiviral activity of the compounds.
This resulted in compounds with a high selective index. One such
compound was 1738
,4,9,9a-hexahydronaphtho[2,3-c]thiophene], with a selective index higher
than 770. The time-of-addition experiment indicated that these compounds
acted at or near the reverse transcription step of the HIV-1 life cycle.
THN derivatives inhibited HIV-1 reverse transcriptase (RT) in vitro at a
concentration of 1 microM. Resistant viruses selected in the presence of
THN derivatives showed some degree of cross-resistance to other
nonnucleoside RT inhibitors, but not to the nucleoside RT inhibitor,
AZT. THN derivatives failed to inhibit replication of pyridinone- and
nevirapine-resistant HIV strains. However, compound 1737 inhibited
replication of a TIBO-resistant strain more effectively than the
wild-type HIV-1. Consistent with this result, compound 1737 also
inhibited TIBO-resistant RT more effectively than the wild-type RT in
vitro. These results suggested that THN derivatives interact with RT in
a manner similar to but slightly different from that of other
nonnucleoside HIV-1 RT inhibitors.
*Anti-HIV Agents *Lignans/PHARMACOLOGY