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from the latex of Calophyllum teysmanni var. inophyllolide.
17
A total of 14 analogs
were synthesized and tested by the NCI primary anti-HIV evaluation using XTT
assay, whereas no compounds exhibited anti-HIV activity superior to the two nat-
ural lead products (1 and 15). Some structure activity requirements were apparent
from the relative anti-HIV potencies of the various analogs. Reduction of the
7,8
-
olefinic bond indicated only a slight change in potency, and a hetero atom is
required at C
12
, for activity such as (
)-12-oxo-calanolide B and (
þ
)-12-oxo-
calanolide A still showed antiviral activity.
Zembower et al.
27
prepared a series of racemic structural analogs of (
)-calanolide
A focused on the modification of the trans-10,11-dimethyldihydropyran-12-ol
ring (ring C) and evaluated their anti-HIV activity using a CEM-SS cytoprotection
assay. Introduction of the extra methyl group into either the C
10
or C
11
position
resulted in only two chiral centers with lowering of the activity relative to (
)-
calanolide A. Substitution of the C
10
-methyl group with an isopropyl chain led to
loss of activity. Analogs containing a cis-relationship between the C
10
and C
11
alkyl
groups were completely devoid of the potency except for the synthetic intermediate
in which the C
12
-hydroxyl group in the ketone form possessed activity less potent
than that of calanolide A with either the C
10
-C
11
-cis-orC
10
-C
11
-trans-relationship.
It is interesting that these two ketones represent the first derivatives in the calano-
lide series to exhibit anti-HIV activity while not containing a C
12
-hydroxyl group
and including a cis-relationship between the C
10
- and C
11
-methyl groups.
Some structural modifications of racemic calanolide A have been studied by
us.
58
Removal of C
11
-methyl or methyl groups at both C
11
and C
6
positions main-
tains the basic stereochemistry of (
)-calanolide A as well as evaluates their anti-
HIV activity. (
)-C
11
-demethyl calanolide A and (
)-calanolide A exhibited similar
potencies, whereas the 6,6,11-demethyl calanolide A also had diminished activity.
The primary biological indicated that two methyl groups in the C
6
position might be
necessary for antiviral activity.
Recently Sharma et al.
59,60
envisaged that replacement of the coumarin ring
oxygen atom (at position C
1
) of calanolide A with the nitrogen atom lead to dipyr-
anogsuinolinone with a calanolide skeleton, namely, aza-calanolide A. The EC
50
value of (
)-aza-calanolide A (0.12 mM) is much lower than that of the natural
product (
)-calanolide A (0.27 mM). The IC
50
value for (
)-aza-calanolide A
and (
þ
)-calanolide A are 15 mMand23mM, respectively. Thus, these compounds
were useful as an anti-HIV agent and were found to possess a better therapeutic
index than calanolide A.
8.6
CONCLUSION
(
þ
)-Calanolide A (1), (
)-calanolide B (15), and (
þ
)-inophyllum B (3) are the
most potent candidates of anti-HIV-1 agents among Calophyllum coumarins. (
þ
)-
calanolide A (1) is the only naturally occurring anti-HIV agent to be at an advanced
stage of a phase II clinical trial, but it has been obtained in relatively low yield
isolated from Calophyllum lanigerum. Several synthetic routes for preparation of
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