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J. Su et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3447–3451
F
F
F
F
F
COOMe
COOMe
COOMe
NaH, Tf2NPh
THF, rt, 48 h
B(OH)2
TfO
O
F
Pd(PPh3)4, Na2CO3
Tol:EtOH (3.5:1)
55oC, 20 h
90%
5
3
4
68%
LiAlH4, THF
-78oC to 0oC
30 min
F
F
F
F
KOtBu, THF
0oC, 15 min
O
O
F
MCPBA, DCM
OH
O
rt, 30 min
100%
53%
95%
F
F
6
8
7
F
F
O
O
O
3 eq 4-ClPhSH, 1 eq BH3.THF
NaH, BrCH2CO2Me, TMAB
THF, rt to 78 0C, 16 h, 58%
OH
O
O
hexane, rt, 14 h, 88%
cis :trans = 5 : 2
F
S
F
S
Ar
Ar
9
10
Ar = 4-ClPh
F
F
O
O
1. LiAlH4, -78 °C to -20 0C, 1.5 h, 91%
2. MsCl, Et3N, 0 0C, 2 h, 95%
a-f
O
O
OMs
X
F
S
F
O2S
Ar
12
Ar
11
X = SEt
13 X = SO2Et
14 X = SiPr
Reagents and conditions: (a). EtSH (or iPrSH)/NaOH/EtOH, 80 0C, 12 h, 85%, 80%
15
X = SO2iPr
16 X = SO2Me
17 X = SO2NHMe
12 14 13
respectively; (b). MCPBA, DCM, rt, 12 h, 85% for
15
, 85% for ; (c).
for
,
MeSO2Na, 70 0C, 12 h, 63% for 16; (d), NaN3/DMF, 72 0C, 2.5 h, 92%; PPh3, THF,
H2O, 80 0C, 12 h, 67% for 19; then MsCl or Tf2O, Et3N, 56% for 22, 75% for 23; (e),
MeNH2 or Me2NH, 40 0C, 16 h , 58% for 20, 58% for 21; (f), KSAc/DMF, 80 0C, 2 h;
K2CO3/MeOH, rt, 4 h, 60%; KNO3/SO2Cl2/MeCN, 45 min; MeNH2 or Me2NH, rt, 0.5 h,
18
X = SO2NMe2
19 X = NH2
20 X = NHMe
21
X = NMe2
22 X = NHSO2CF3
23 X = NHSO2Me
17
18
.
40% for
, 68% for
Scheme 1. Synthesis of C-6 analogs.
1, the C-6 side chain was installed and the sulfone group was intro-
duced. Deprotection of the ketal group provided the ketone analogs
36 and 39, which, could be further reduced to the alcohol analogs
37 and 40. A sulfonamide analog 41 was also synthesized using the
synthetic route for compound 22 (Scheme 1). To synthesize C-8
sulfonamide analogs 43–46, the C-8 alcohol 28 was first converted
to the azide via the mesylate intermediate, followed by reduction
to afford the primary amine 42. Compound 42 was then converted
to the corresponding targets 43 to 46.
Comparison of compounds 27a and 27b demonstrated the
importance of the relative stereochemistry at C-5 and C-6. While
the trans isomer 27b was completely inactive (IC50 = 3000 nM),
the cis isomer 27a had a IC50 of 21 nM, comparable to its C-6 des
hydroxy analog 32 (IC50 = 13 nM). The IC50 values could be also
influenced by substituents at the C-8 position: while installing a
ketone group did not change the IC50 values (compounds 27a
and 32 vs 33), the bulky ketal group was not tolerated at all (com-
pounds 26a vs 33). The stereochemistry at the C-8 position could
also make a difference: the cis diol 29 (IC50 = 29 nM) retained the
binding activity while the trans diol 28 had an IC50 of 363 nM, a
12-fold decrease.
Other similar targets synthesized according to Schemes 1–3 are
listed in Figure 2 except for compounds 32 and 33 which were re-
ported earlier.3
All compounds were tested in the in vitro membrane Ab40 inhi-
bition assay11 and the biological data are shown in Table 1.12 While
analogs 12 and 14 with a C-6 alkyl sulfide group showed moderate
activities (IC50 ꢀ170–180 nM, Table 1), their corresponding sulfone
analogs 13, 15 and 16 were 10- to 20-fold more active (e.g., 15 had
IC50 = 8 nM). The sulfonamide analogs 17 and 18 were about 5-fold
less active than the sulfone analogs. Interestingly, the reversed
methanesulfonamide analog 23 retained the strong inhibition
(IC50 = 26 nM) whereas another analog –NHTf 22 was 11-fold less
active. The side chain at the C-6 position also tolerated a basic
amine group. For example, the primary amine 19 had IC50 = 12 nM
while the secondary amine 20 and the tertiary amine 21 were 3-
fold less active.
The combination of the C-6 side chain and C-8 substituents did
not have a synergistic effect on the Ab40 inhibition. For example,
with an alkylsulfone group on the C-6 side chain, the presence of
a ketone or hydroxyl group led to a 10-, 6-fold decrease, respec-
tively (compounds 36/37 vs 13, 39/40 vs 15). The presence of –
NHTf on the C-6 side chain along with the C-8 hydroxy group led
to the loss of activity for 41 (>13-fold drop compared with 22).
On the other hand, the combination of just a C-6 hydroxy group
and a C-8 sulfonamide group was well tolerated. Among them, The
NHTf 2 and the cyclopropylsulfonamide 45 had IC50 <30 nM.
Increasing the pKa of the sulfonamide NH resulted in higher IC50
values (compounds 43, 44 vs 2).13 Replacing the cyclopropylsulf-
onamide with cyclobutylsulfonamide led to a 7-fold decrease in