Chemistry Reference
In-Depth Information
TABLE 8-1. Anti-HIV-1 Activity of (
)-1,(
þ
)-1, and (
)-Calanolide A [(
)-1]
AZT
e
DDC
e
Strain/cell
(
)-1
(
þ
)-1
(
)-1
RF
11
/CEM
EC
50
(mM)
0.486
0.267
0.023
0.189
IC
50
(mM)
22.81
22.96
18.70
301.60
47.34
TI
d
47
86
13 113
250
III
B
/MT2
EC
50
(mM)
0.108
0.053
0.029
0.900
IC
50
(mM)
6.86
14.80
7.31
51.64
83.80
TI
d
64
279
1780
93
H112-2
a
/
EC
50
(mM)
0.135
0.107
0.037
1.562
MT2
IC
50
(mM)
6.53
7.15
6.21
119.84
258.97
TI
d
48
67
3236
166
G910-6
b
/
EC
50
(mM)
0.108
0.027
0.994
MT2
IC
50
(mM)
7.42
7.17
6.16
131.71
212.10
TI
d
69
266
213
A17
c
/MT2
EC
50
(mM)
0.297
0.427
0.014
0.331
IC
50
(mM)
6.94
6.99
5.89
83.44
134.93
TI
d
23
16
5960
408
a
Pre-AZT treatment isolate.
b
Post-AZT treatment isolate.
c
Pyridinone-resistant isolate.
d
TI
¼
IC
50
/EC
50
.
e
AZT and DDC were positive control drugs.
(EC
50
¼
0.297 mM) against the pyridinone-resistant strain A17 was more compar-
able with that of (
þ
)-1 (EC
50
¼
0.427 mM).
It was discovered that the synthetic intermediate [12-oxo-(
)-calanolide A, (3)]
exhibited anti-HIV-1 activity
27
with one less chiral center than calanolide A. This
unique feature makes 3 an attractive candidate for drug development because it can
be conveniently prepared. Therefore, (
)-3,(
þ
)-3, and (
)-3, were prepared and
evaluated for antiviral activities against HIV-1, simian immunodeficiency virus
(SIV), and HIV-2 using CEM-SS cells infected in various laboratories and clinical
isolates of viruses.
28
The antiviral results were summarized in Table 8-2 and indi-
cated that these 12-oxo-calanolide A were active against both HIV-1 and SIV, but
they were inactive against HIV-2. It was also worthy to note that compound 3 was
the first reported calanolide analog capable of inhibiting SIV.
TABLE 8-2. Antiviral Activity of (
)-, (
þ
)-, and (
)-12-Oxo-calanolide A (3) Against
Various Infected CEM-SS Cells
EC
50
(mM)
DDC
a
Virus
(
)-3
(
þ
)-3
(
)-3
(
þ
)-Calanolide A
HIV-1 (R
F
)
0.4
0.9
3.41
0.05
0.27
HIV-1(III
B
)
0.51
1.0
1.88
0.02
0.17
HIV-1(SK1)
0.17
0.17
0.27
0.05
0.14
SIV(Delta)
1.24
1.66
6.12
0.19
inactive
ND
b
HIV-2(ROD)
5.57
15.90
0.03
inactive
a
DDC was used as a positive control drug.
b
ND: not determined.
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