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In-Depth Information
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2 (cis-3'R, 4'R)
3 (cis-3'S, 4'S)
4 (trans-3'R,4'S)
5 (trans-3'S, 4'R)
Figure 9-2. Structures and 3-D orientation of DCK stereochemical isomers (2-5).
conformationally flexible, and its terminal carbon atoms are disordered over two
orientations, whereas in 2, the 4
0
-camphanoyl group neighbors another bulky cam-
phanoyl substituent making the isovaleryl moiety more rigid.
24
The study data sug-
gest that a rigid stereochemistry of 3
0
and 4
0
-configured khellactone derivatives is
crucial for anti-HIV activity.
9.2.2.2 3
0
R,4
0
R Modification
Several compounds with C-3
0
R,4
0
R small or bulky substituents were then designed
and synthesized
25
(Figure 9-4). When the two (
)-camphanoyl groups in DCK
were
replaced
with
(
þ
)-camphanoyl
groups
(43),
the
anti-HIV
activity
TABLE 9-1. Anti-HIV Activities of Khellactone Derivatives
a,22
No.
IC
50
(mM)
b
EC
50
(mM)
c
TI
d
Suksdorfin(1)
>
52
2
:
6
2
:
1
30
:
6
22
:
4
2
:
56
10
4
1
:
37
10
5
2
35
3
1700
51
33.3
4
>
6.4 but
<
32
>
6.4 but
<
32
1
5
>
32
32
1
8
14
7
2
10
101
7
14.4
11
16.5
4.7
3.5
<
1.4
>
2.2
13
3.1
AZT
1875
0.045
41,667
a
Inhibitory of HIV-1 IIIB in H9 lymphocytes.
b
Concentration that inhibits uninfected H9 cell growth by 50%.
c
Concentration that inhibits viral replication by 50%.
d
Therapeutic Index, TI
¼
IC
50
=
EC
50
.
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