Chemistry Reference
In-Depth Information
cycle.
12-14
A small branch of the coumarin family, khellactones, are notable for
extensive bioactivities, including anti-HIV, antitumor promoting,
15
and antiplatelet
aggregation
16
properties.
In 1994, Lee et al. reported on the anti-HIV activity of suksdorfin(1), a dihydrose-
selin type angular pyranocoumarin, isolated from the methanolic extract of Lomatium
suksdorfii through BDFI. It suppressed viral replication in 11 separate acute HIV-1
IIIB
infections of H9 lymphocyte cells with an average EC
50
value of 2.6
2.1 mM. It also
suppressed acute HIV-1 infections in fresh peripheral blood mononuclear cells, mono-
cyte/macrophages, and U937 cells, a promonocytic cell line.
17
Suksdorfin(1)repre-
sents a new class of potent anti-HIV agents that is structurally unique compared
with other known anti-AIDS drugs; therefore, 1 has been chosen as lead compound
for various structural modifications, following the principles of analog design.
O
O
O
4′
3′
O
O
O
O
Suksdorfin (
1
)
9.2.2 Pyrano-3
0
,4
0
Stereoselectivity and Modification
9.2.2.1 3
0
,4
0
Stereoselectivity
According to an almost universally accepted opinion, stereoisomers of an organic
molecule should be anticipated to frequently exhibit widely different and unpredict-
able pharmacological effects.
18-20
The two chiral centers of suksdorfin(1), C-3
0
and C-4
0
, both possess R configurations. Our first SAR effort was to elucidate
the stereochemical requirement of these two positions, as a different configuration
changes the orientation and shape of the whole molecule. Huang et al. synthesized a
series of khellactone derivatives, including all four stereochemical isomers, 3
0
,4
0
-
cis or trans (2-38) (Figures 9-2 and 9-3).
21,22
Some cis-3
0
,4
0
-substituted com-
pounds showed activity against HIV-1 in H9 lymphocytes, which are listed in
Table 9-1. Among them, 3
0
R,4
0
R-di-O-(
)-camphanoyl-(
þ
)-cis-khellactone
(DCK, 2) had an EC
50
of 2
:
6
10
4
mM and TI of 137,000, and it was much
more potent than the remaining stereo-isomers, 3 (3
0
S,4
0
S,EC
50
51 mM and TI
33), 4 (3
0
R,4
0
S,EC
50
6.4 mM and TI 1), and 5 (3
0
S,4
0
R) (EC
50
32 mM and TI 1).
The three-dimensional (3-D) orientations of the four DCK stereochemical isomers
(Figure 9-2), generated by Tripos Sybyl software,
23
showed different molecular
orientations and shapes. Therefore, 3
0
R,4
0
R DCK (2) may fit the putative receptor,
whereas the other three configurations do not. Thus, the low anti-HIV activity of most
synthetic khellactone analogs may be attributed to racemization (Figure 9-3).
22
The rigid (
)-camphanoyl moiety in DCK (2) contains the isovaleryl group. An
x-ray crystallographic analysis confirms that the isovaleryl group in 1 is more
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