Chemistry Reference
In-Depth Information
TABLE 7-1. Pharmacological Activity of Methoxy- and Ethoxy Analogs of
GA, GB, and GC
O
R
2
O
O
R
1
10
O
O
1
O
Me
7
HO
O
R
3
O
Compounds
R
1
R
2
R
3
IC
50
(mM)
GA
H
H
H
0.74
GB
OH
H
H
0.25
GC
OH
H
OH
7.1
10-Me-GA
H
CH
3
H
13
10-Et-GA
H
CH
3
CH
2
H
62
1-Me-GB
OCH
3
H
H
0.66
10-Me-GB
OH
CH
3
H
0.29
1-Et-GB
OCH
3
CH
2
H
H
1.1
10-Et-GB
OH
CH
3
CH
2
H
7.2
1-Me-GC
OCH
3
H
OH
4.2
10-Me-GC
OH
CH
3
OH
3.0
1-Et-GC
OCH
3
CH
2
H
OH
8.5
10-Et-GC
OH
CH
3
CH
2
OH
9.3
mixtures of 1- and 10-substituted analogs that were separated by column chroma-
tography.
89
Interestingly, 1- and 10-methoxy analogs of GB were equipotent to GB,
whereas the corresponding ethoxy analogs were less potent. The 10-substitued ana-
logs of GA were significantly less potent than GA, whereas methyl analogs of GC
were more potent and ethyl analogs were equipotent to GC (Table 7-1).
Corey and Gavai investigated various intermediates in the total syntheses of
GA
54
and GB,
55
and they found that the lactone F was not essential for activity
and could be replaced by other lipophilic groups,
90
whereas the unique tert-butyl
group was critical for activity.
91
Villhauer and Anderson synthesized the CDE
ring system of ginkgolides, which was ineffective as a PAF receptor antagonist.
92
The most comprehensive SAR study on ginkgolides and PAF receptor was per-
formed by Park et al., who synthesized more than 200 derivatives of GB, with
particular focus on aromatic substituents at 10-OH.
93
These derivatives were gen-
erally synthesized by treatment of GB with a base and a benzyl halide derivative
providing, in most cases, selective derivatization at 10-OH. Whereas GB had an
IC
50
ΒΌ
0.258 mM, most 10-O-benzylated derivatives were more potent, including
10-(3,5-dimethyl-2-pyridinyl)-methoxy-GB (IC
50
of 0.0245 mM) that was ten-fold
more potent than GB. The same group also investigated elimination products of
GB, as well as derivatives that were bridged between 1- and 10-OH, but these
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