Chemistry Reference
In-Depth Information
TABLE 9-6. Anti-HIV Activity of DCP Analogs (107-124)
43
Non-drug-Resistant Strain
a
M
ultiple RT Inhibitor Resistant Strain
b
Compound
IC
50
(mM)
EC
50
(mM)
TI
IC
50
(mM)
EC
50
(mM)
TI
107
c
14.20
0.0013
11,100
NS
108
14.70
0.00099
14,800
3.14
1.28
2.5
109
>
35.82
1.54
23.3
NS
110
27.30
0.0031
8,600
11.8
0.19
62.5
111
37.16
0.00032
116,200
43.08
0.06
718
112
>
37.65
0.020
1,860
37.65
0.139
272
113
33.4
0.07
483
>
15.04
0.14
>
111.1
114
15.1
0.1
151
>
12.5
0.37
>
34
115
>
35.82
0.129
>
277
12.2
0.17
71
116
11.3
0.007
1,500
4.72
0.31
15
117
>
35.4
1.62
22
>
14.15
7.36
1.9
118
>
50.15
2.29
21.9
>
40.16
2.2
18.2
119
40.68
0.88
46
17.1
0.30
56.3
120
>
32.15
0.0057
5,600
13.0
0.59
22
>
46.3
>
18.5
>
66.7
121
0.25
182
0.28
>
43.9
>
17.52
>
16.1
122
0.62
70
1.09
123
>
44.60
2.24
20
6.25
4.46
1.4
124
>
42.47
1.68
25.3
NS
DCK (2)
d
>
16.1
0.049
>
328
>
16.1
12.06
1.3
53
e
>
39.3
0.0059
>
6,660
>
15.7
9.43
1.7
All data presented in this table are averaged from at least two separate experiments.
a
This assay was performed in H9 lymphocytes by Panacos, Inc., Gaithersburg, MD.
b
This assay was performed in MT-4 cell line by Dr. Chin-Ho Chen, Duke University, NC.
c
Previously obtained and published values: EC
50
¼
0.00068 mM and TI
¼
14
;
500
:
42
d
Previously obtained and published values: EC
50
¼
0.000256 mM and TI
¼
1
:
37
10
5
:
22
e
Previously obtained and published values: EC
50
¼
1
:
83
10
6
mM and TI
¼>
6
:
89
10
7
.
25
NS, No Suppression at 10 mg/mL.
3
0
-camphanoyl-2-substituted compounds. Furthermore, from comparison of EC
50
and IC
50
values for compounds 108 (3-methyl) and 110 (2-methyl), substitution
on the 2-position seems to increase the activity against a multi-RT inhibitor-resis-
tant strain and decrease the cytotoxicity. Based on these data, a hydrophobic moi-
ety, either aliphatic or phenyl, on C-2 is crucial for anti-HIV activity against the
multi-drug-resistant HIV strain and may increase binding of these compounds to
a putative hydrophobic cleft.
43
9.2.3.5 Other Modifications
Homologation of an alkyl chain and alteration of ring size are also useful
approaches in analog design. Therefore, 3
0
R,4
0
R-di-O-(
)-camphanoyl-2
0
,2
0
-
dimethylnaphtho[5,6-a]pyran (125), 3
0
R,4
0
R-di-O-(
)-camphanoyl-2
0
,2
0
-dimethyl-
dihydropyrano[2,3-e]-1-indanone (DCI, 126), and three compounds with opened
A
ring
(127-129)
were
designed
and
synthesized.
These
compounds
vary
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