RECENT PROGRESS AND PROSPECTS ON PLANT-DERIVED ANTI-HIV AGENTS AND ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 374

of action of this compound, a time-of-addition study was performed, where the
point in viral replication inhibited by 102 was compared with the inhibitors acting
at attachment (Chicago Sky Blue) or reverse transcription (AZT 47 and nevira-
pine 48 ). This study indicated that 102 acts at a point in the virus life cycle imme-
diately after the target for the RTIs AZT and nevirapine. Additional mechanism of
action studies are ongoing, and preliminary data suggest that 102 inhibits the pro-
duction of double-stranded viral DNA from the single-stranded DNA intermediate,
in contrast to traditional RT inhibitors that block the generation of single-stranded
DNA from the RNA template. 39
Low water solubility, less potency against drug-resistant HIV strains, and fast
metabolism are three main obstacles that limit the development of DCK analogs.
Additional analog design is likely to use DCP as a new lead to increase the potency
against drug-resistant viral strains and improve water solubility and pharmacologi-
cal properties.

9.3 BIPHENYL DERIVATIVES AS ANTI-HIV AGENTS

9.3.1 SAR Analysis of Naturally Occurring Dibenzocyclooctadiene Lignans

In our previous search for natural products as anti-AIDS agents, an ethanolic extract
of the stems of Kadsura interior showed significant activity. The BDFI led to the
isolation of 12 lignans, including two new compounds. Seven of them showed HIV-
1 suppression activity in H9 lymphocytes. 49,50 Among them, gomisin G (135,
Figure 9-8) showed the most potent anti-HIV activity, with EC 50 and TI values
of 0.011 mM and 300, respectively. Several other lignans also showed moderate
activities; therefore, modifications were conducted on this compound type.
Natural products 130-140 are dibenzocyclooctadiene lignans (Figure 9-8).
Structurally, they contain a linked biphenyl or phenyl/ketocyclohexadiene system,
which can have either an S-(130-136)orR-configuration (137-140). Each ring
is substituted at positions 1, 2, 3 and 12, 13, 14 with combinations of methoxy,
methylenedioxy, or hydroxy groups. Four carbons C-6 C-9 and the biphenyl link-
age (C-5a, C-5, C-10, and C-10a) form a cyclooctadiene ring. 51,52 In all cases, posi-
tions 7 and 8 of this ring each bear one methyl group and they have a-methyl at
C-8, but a different configuration at C-7. Heteroclitin F (141) has a tetrahydrofuran
ring spanning the biphenyl linkage, and phenyl A is opened between C-2,3, which
is called a C-2,3 seco-type. 50 The biphenyl structure feature is needed for the anti-
viral activity because 141 was inactive. However, the biphenyl configuration does
not affect the activity. In Table 9-7, which lists the activities of lignans that showed
EC 50 values lower than 10 mM, five compounds have an S-biphenyl and three pos-
sess R-configuration. Likewise, the configuration of the 7-methyl does not play a
role in activity, because 130 and 132 (7a-methyl) showed similar activity to 136
(7b-methyl). Two C-6b substituents were found in these compounds, angeloyl
and benzoyl (Bz). Compounds with an angeloyl group, 131 and 134, did not