RECENT PROGRESS IN CALOPHYLLUM COUMARINS AS POTENT ANTI-HIV AGENTS - Medicinal Chemistry of Bioactive Natural Products - page 326

might overcome the virus-drug resistance problem by focusing on either novel targets or
new compounds capable of suppressing HIV strains that are resistant to the currently
used anti-HIV drugs. Therefore, medicinal chemists are interested in the development
of novel anti-HIV agents that might be particularly effective in controlling strains of
HIV that are resistant to the current NRTIs, NNRTIs, PIs, and so on.
Natural products have been important sources of new pharmacological active
agents. Plant-derived products have led to the discovery of many clinically useful
drugs for the treatment of human diseases such as antitumor and anti-infective
drugs. Coumarins are well-known natural products displaying a broad range of bio-
logical activities. 5,6 Coumarin derivatives have been extensively used as therapeutic
agents, active media for tunable dye lasers, optical bleaching agents, luminescent
probes, and triplet sensitizers. 7 In 1992, Kashman et al. 8 first reported on a novel
dipyranocoumain, calanolide A (1), isolated from the Malaysia tree Calophyllum
lanigerum, and Patil et al. 9 reported on a related compound inophyllum B (3)
from Calophyllum inophyllum. Both of them are representatives of a distinct class
of NNRTI. Therefore, scientists are interested in the plant of genus Calophyllum.
The chemical structures of naturally occurring coumarins isolated from Calophyl-
lum species are summarized in Structure 8-1.
Numerous dipyranocoumarins have been isolated from different species of Calo-
phyllum. According to their chemical skeleton, they have three heterocycle rings,
ring B, C, and D, constructed from a phloroglucinol core A. These compounds fall
into three basic structural types: (1) tetracycle dipyranocoumarins in which the D
rings have a gem-dimethyl group, such as ( þ )-calanolide A (1), ( þ )-calanolide B
(2), ( þ )-inophyllum B (3), and ( þ )-cordatolide A (5); (2) tetracyclic dipyranocou-
marins with reversed D and C pyran rings; namely, the gem-dimethyl is present in
ring C, as in the ( þ )-pseudocalanolide C (21) and ( þ )-pseudocalanolide D (25); and
(3) tricyclic pyranocoumarins, for example, ( þ )-calanolide E (26) and ( þ )-corda-
tolide E (27), which contain a noncyclized equivalent of ring C of the calanolide
tetracyclic structures. Individual members of the groups vary with respect to the
C-4 substituent on the lactone ring (ring B) of the coumarin, where n-propyl (calano-
lides), phenyl (inophyllums), and methyl groups (cordatolides) may be encountered.

6

R

O

7

5

D

4

8

3

A

B

O O O

2

9

C

1

12

R 1

10

11

R 2

(I)

1 R ¼ n-C 3 H 7 R 1 ¼ OH R 2 ¼ H( þ )-calanolide A 8
2 R ¼ n-C 3 H 7 R 2 ¼ OH R 1 ¼ H( þ )-calanolide B 8,10
Scheme 8-1.

Chemical structures of naturally occurring Calophyllum coumarins.