ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) ACTIVITIES OF HALOGENATED GOMISIN-J DERIVATIVES, NEW NONNUCLEOSIDE INHIBITORS OF HIV TYPE-1 REVERSE-TRANSCRIPTASE
T. Fujihashi et al., ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) ACTIVITIES OF HALOGENATED GOMISIN-J DERIVATIVES, NEW NONNUCLEOSIDE INHIBITORS OF HIV TYPE-1 REVERSE-TRANSCRIPTASE, Antimicrobial agents and chemotherapy, 39(9), 1995, pp. 2000-2007
Halogenated gomisin J (a derivative of lignan compound), represented b
y the bromine derivative 1506 {(6R, 7S, etramethoxy-6,7-dimethyl-5,6,7
,8-tetrahydrodibenzo [a,c] cyclooctene}, was found to be a potent inhi
bitor of the cytopathic effects of human immunodeficiency virus type 1
(HIV-1) on MT-4 human T cells (50% effective dose, 0.1 to 0.5 mu M).
Gomisin J derivatives were active in preventing p24 production from ac
utely HIV-1-infected H9 cells. The selective indices (toxic dose/effec
tive dose) of these compounds were as high-as >300 in some systems. 15
06 was active against 3'-azido-3'-deoxythymidine-resistant HIV-1 and a
cted synergistically with AZT and 2',3'-ddC. 1506 inhibited HIV-1 reve
rse transcriptase (RT) in vitro but not HIV-1 protease. From the time-
of-addition experiment, 1506 was found to inhibit the early phase of t
he HIV life cycle. A 1506-resistant HIV mutant was selected and shown
to possess a mutation within the RT-coding region (at position 188 [Ty
r to Leu]). The mutant RT expressed in Escherichia coil was resistant
to 1506 in the in vitro RT assay. Some of the HIV strains resistant to
other nonnucleoside HIV-1 RT inhibitors were also resistant to 1506.
Comparison of various gomisin J derivatives with gomisin J showed that
iodine, bromine, and chlorine in the fourth and ninth positions incre
ased RT inhibitory activity as well as cytoprotective activity.