RECENT PROGRESS IN CALOPHYLLUM COUMARINS AS POTENT ANTI-HIV AGENTS - Medicinal Chemistry of Bioactive Natural Products - page 333

the C12-epimer of ( þ )-inophyllum B (3), and inophyllums G-1 (19) and G-2 (20)
were novel compounds. 9 All 11 natural products were evaluated for their inhibitory
activity against HIV-1 RT. Among the most potent active compounds, inophyllum B
(3), and inophyllum P (4), inhibited HIV-1 RT with IC 50 values that were 38 nM and
130 nM, respectively, and both were active against HIV-1 in cell culture with EC 50
values that were 1.4 mM and 1.6 mM, respectively. However, both inophyllum B (3)
and inophyllum P (4) possessed the trans-C 10 ,C 11 -dimethyl chromanone ring,
which is different from the stereochemistry of the hydroxy group at the C 12 posi-
tion. The stereochemistry of the hydroxy group at the C 12 position was not critical
for antiviral activity, but the subsituents of carboxyl group at the C 12 position low-
ered the activity significantly. For example, inophyllum C (11) and Inophyllum E
(12) were much less active, whereas the closely related ( þ )-inophyllum D (18) and
( þ )-inophyllum A (17) possessing a cis-C 10 ,C 11 dimethylchromanol ring were less
active. Furthermore, ( )-inophyllum P 33 (soulattrolide, 16), a close structural
resemblence to ( )-calanolide B (15), was found to be a potent inhibitor of HIV-
1 RT with an IC 50 of 0.34 mM when HIV-RT was assessed for RNA-dependent DNA
polymerase (RDDP). No appreciable activity was observed toward HIV-2 RT and
avian myeloblastosis virus reverse transcriptase (AMVRT). The absolute configura-
tion of ( )-inophyllum P as (10S, 11R, 12S) and other structurally related HIV-1
inhibitors, including ( þ )-inophyllum B (3), ( þ )-inophyllum P (4), ( þ )-calanolide
A(1), ( þ )-calanolide B (2), ( )-calanolide B (15), ( þ )-cordatolide A (5), and
( þ )-cordatolide B (6) were also assigned. 34

8.2.3 Anti-HIV-1 Activity of Cordatolides

( þ )-Cordatolide A (5) and ( )-cordatolide B (6) were first isolated from Calophyl-
lum Cordato-oblongum 12,13 for biological evaluation and found to mediate signifi-
cant inhibition of HIV-1 RT with IC 50 values of 12.3 and 19.0 mM, respectively. 35
( þ )-Cordatolide A (V) with the 12b-hydroxy configuration was somewhat more active
than the corresponding 12a-hydroxy Cordatolide B (6). However, ( þ )-cordatolide
A has the same stereochemistry as ( þ )-calanolide A (1) and ( þ )-inophyllum B
(3), and the activity with inhibition of HIV-1 RT was much lower than calanolide
A(1) and inophyllum B (3), but there is no report on the anti-HIV-1 activity of
cordatolide A and B in the cell line. It seems to be that the substituents located
at the C 4 position are important for antiviral activity because the propyl group at
C 4 in calanolide A (1) or the phenyl group in inophyllum B (3) exhibited the highest
activity, which indicates that the bulky substituents at the C 4 position may be neces-
sary for the antiviral activity.

8.3 PHARMACOLOGY OF CALANOLIDES

8.3.1 Pharmacology of ( þ )-Calanolide A

( þ )-Calanolide A (1) inhibited HIV-1 in cell culture but was inactive against HIV-2
or SIV. In the viral life-cycle investigations, it was demonstrated that calanolide A