RECENT PROGRESS AND PROSPECTS ON PLANT-DERIVED ANTI-HIV AGENTS AND ANALOGS - Medicinal Chemistry of Bioactive Natural Products - page 379

with poly(rC)-oligo(dG) as template-primer than with poly(rA)-oligo(dT). In con-
trast, for 164, the enzyme was about six times more sensitive with poly(rA)-oli-
go(dT). Nevirapine, an NNRTI, demonstrated more inhibitory activity using
poly(rC)-oligo(dG) as template-primer than poly(rA)-oligo(dT). 59 Both compounds
demonstrated potent inhibitory effects against HIV-1 RT-associated DNA polymer-
ase activity using poly(dA)-oligo(dT) as a template-primer, with IC 50 values of
0.056 and 0.048 mM, respectively. They also displayed similar inhibition against
HIV-RT-associated RNase H activity when poly(rG)-poly(dC) was used as the sub-
strate and Mn 2 þ (0.4 mM) was used as the divalent cation. However, when
poly(rA)-poly(dT) was used as the substrate or Mg 2 þ was used as the divalent
cation, no inhibition was observed. Because RT plays an important role in HIV
replication, the potent inhibitory activity of 163 and 164 against the enzyme-cata-
lyzed DNA direct DNA synthesis might be related to their anti-HIV activity. 53

9.4 TRITERPENE BETULINIC ACID DERIVATIVES
AS ANTI-HIV AGENTS

Triterpenes represent a structurally varied class of natural products existing in var-
ious plant species. Thousands of triterpenes have been reported with hundreds of
new derivatives described each year. 60,61 Some naturally occurring triterpenes exhi-
bit moderate anti-HIV-1 activity and, therefore, provide good leads for further drug
development because of their unique mode of action and chemical structures. 62
Anti-HIV triterpenes were found to block HIV entry, including absorption (glycyr-
rhizin 63,64 ) and membrane fusion (RPR103611 65 ), inhibit RT (mimusopic acid 66 )
and PR (ganoderiol, 67 geumonoid, 68 ), and act during viral maturation (DSB 69 ).
Here, we will mainly focus on the modification of betulinic acid and new mechan-
isms of action of RPR103611, IC9564, and DSB.
Lupane is a pentacyclic triterpene with a five-membered E ring. Two members of
this group, 3b-hydroxy-lup-20(29)-en-28-oic acid (betulinic acid, BA, 182) and
platonic acid (185), were first reported to reduce HIV IIIB reproduction by 50% in
H9 lymphocytes, with EC 50 values of 1.4 and 6.5 mM, respectively. With an addi-
tional hydroxy group at C-2, alphitolic acid (183) displayed much lower anti-HIV
activity (EC 50 ¼ 42.3 mM) (Figure 9-10). 70 BA (182) has been widely investigated
for significant chemical, spectral, and biological data. Several patents are related to
the pharmaceutical application of BA for the treatment of cancer, 71,72 viral infec-

tions, 72,73 hair loss, 74,75 and other conditions. 76

9.4.1 Betulinic Acid Derivatives as Entry Inhibitors

9.4.1.1 Modification of Ring A
A group of scientists at the University Leuven, Belgium, observed weak inhibition
of HIV-1 PR of betulinylglycine (184) from a high throughput screening; therefore,
they modified the C-28 side chain. 77 Interestingly, no significant improvement of

the anti-protease activity was achieved. However, some active analogs were