Chemistry Reference
In-Depth Information
Epo B is closely related to its x-ray crystal structure; in particular, the three bonds
between C8/C9, C9/C10, and C10/C11 all adopt an anti-periplanar conformation.
The model suggested that the incorporation of meta-substituted phenyl rings in
the C9 to C12 segment, such as in compounds 2 or 3, should lead to a stabilization
of the purported bioactive conformation in this potentially flexible region of
natural epothilones. While the synthesis and biological evaluation of 3 has been
reported by the Schering AG group,
66
we have recently described the synthesis of
analog 8.
81
Unfortunately, 2 and 3 were found to be substantially less active than
Epo B or D (2; Ref. 81) or to exhibit ''reduced'' activity (11;Ref.66).Morespecific
data are not available from Ref. 66.
S
S
N
HO
N
OH
O
O
O
O
HO
O
OH
2 3
In contrast to these disappointing early findings, several highly potent epothilone
analogs with structural variations in the C9-C11 trimethylene region have been
described more recently, some of which have also been found to exhibit favorable
in vivo pharmacological properties.
R
S
S
HO
10
N
N
9
O
HO
O
O
O
HO
O
H
R = CH
3
:
5
R = CF
3
:
6
4
O
S
S
HO
N
N
HO
O
O
O
O
HO
O
H
7
8
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