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OH
O
1
C
8
H
17
24
O
10
O
O
15
OH
232a
(15
R
, 24
R
, 36
S
)
232b
(15
S
, 24
R
, 36
S
)
232d
(15
R
, 24
S
, 36
S
)
232c
(15
S
, 24
S
, 36
S
)
HO
HO
HO
HO
( )
10
( )
10
CO
2
Me
CO
2
Me
S
R
O
O
233
235
O
O
R
S
C
8
H
17
X
CHO
CHO
C
8
H
17
X
O
O
OMOM
OMOM
X = OH,
234a
X = I,
234b
X = OH,
236a
X = I,
236b
1. Bu
2
SnO
CHCl
3
/MeOH, reflux
C
9
H
19
OH
CO
2
Me
1. LDA
(
s
)-Me(OTHP)CHCHO
O
232c
235
( )
12
O
S
S
2. CsF/DMF,
236b
2. 9% H
2
SO
4
, THF
3. Tf
2
O, NEt
3
, DCM;
4. HCl, MeOH
237
OMOM
Scheme 10-40. Synthesis of second generation of mimics 232a-d by Yao et al.
were active even under the mM scale. Most importantly, these mimics showed cyto-
toxic selectivity; they were active toward the HCT cell but inactive toward the KB
and A2789 cells. In contrast, the control agent adriamycin displayed higher activ-
ities, but it did not differentiate these cells. It is noteworthy that these mimics had
no cytotoxicity toward normal human cells. Among these four mimics, 232c
showed somewhat better activities, which might be attributed to their different
stereochemistry.
To get more information about the SAR of acetogenin or its mimics, we synthe-
sized 238a-d, which have no butenolide unit, and butenolides 239, which lack the
THF ring or glycol ether unit. These compounds showed no or weak cytotoxicity,
which indicated that both the butenolide segment and the glycol ether unit were
indispensable.
96,97
The stereochemistry of the chiral center in the butenolide
TABLE 10-4. Cytotoxicity of Mimics 232a-d Toward Four Kinds of Cells
EC50 (mgmL
1
)
Compound
KB
A2780
HCT-8
HT-29
6.6
10
2
2.7
10
1
232a
>
1
>
1
9.7
10
2
232b
>
1
>
1
1.1
3.2
10
2
1.1
10
1
232c
>
1
>
1
6.5
10
2
232d
>
1
>
1
7.8
2.89
10
3
1.02
10
3
4.65
10
3
9.8
10
4
Adriamycin
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