Chemistry Reference
In-Depth Information
TABLE 9-7. Anti-HIV Activities of Potent Dibenzocyclooctadiene Lignans and
Biphenyl Derivatives
49,50,53
Biphenyl
Therapeutic
Compound
Configuration
IC
50
(mM)
EC
50
(mM)
Index
130
S
77.3
5.9
13
132
S
104
3.1
33.3
133
S
106
0.96
110
135
S
3.4
0.011
300
136
S
23.2
3.86
6
137
R
112
2.0
56
138
R
21.6
2.4
9
143
R
36
7.2
5
147
13
6
2.2
151
>
140
10
>
14
152
4
2
2
153
30
13
2.3
159
10
5
2
160
>
239
12.0
>
20
163
>
201
1.05
>
190
164
>
174
0.40
>
480
166
>
166
3.3
>
50
176
>
174
3.6
>
48
9.3.2
Structural Modifications
9.3.2.1 Dibromination of Dibenzocyclooctadiene Lignans
Five dibrominated derivatives (142-146, Figure 9-8) were synthesized from
compounds 132 and 137-140, and evaluated for anti-HIV activity.
50
Only 143 had an
EC
50
lower than 10 mM(EC
50
¼
7.2 mMandTI
¼
5); however, it was still less potent
than its parent compound 137 (EC
50
¼
2.0 mMandTI
¼
56, Table 9-7).
9.3.2.2 Biphenyl Derivatives
Because the biphenyl configuration does not affect the antiviral activity of dibenzo-
cyclooctadiene lignans, to simplify the structure and achieve synthetic feasibility,
we turned to modify biphenyl derivatives.
50,53
These derivatives were first designed
and synthesized during the modification of anti-HIV tannins.
54-57
Each aromatic
ring bears three variously substituted phenolic groups (position-4, 5, and 6) and,
thus, are called hexahydroxydiphenyl derivatives (Figure 9-9). Among the ben-
zoyl-substituted biphenyl derivatives (147-157), only 151 demonstrated inhibitory
activity against HIV in acutely infected H9 lymphocytes (EC
50
¼
10 mM) with low
toxicity (IC
50
>
140 mM). The two hydroxymethyl groups at C-2 and C-2
0
seemed
to be essential for specific HIV inhibition. Replacing them with CHO in 152 greatly
increased the toxicity and slightly increased the activity. When bromomethyl at
these positions (153), toxicity increased with no change of potency. No inhibition
was observed with analogs that were mono- or dibrominated at C-3 and C-3
0
and
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