products 19-22 (not shown), which were thermodynamically
derived as evidenced by the predominate trans geometry of
the resulting olefins. Although the yields were not high, they
were well within reported values for less complex sub-
strates.15 With the desired products in hand, solvolysis of
the cyclic carbonates were then performed to furnish the
corresponding diols, 23-26.
Scheme 3. Synthesis of Tether Analogues
To determine their efficacy as Hsp90 inhibitors, 9 and 10
were first evaluated in antiproliferative assays with MCF-7
and SKBr3 breast cancer cells as well as in a Her2 ELISA
1
6,17
protocol.
To our surprise, the compounds derived from
phthalic acid produced no activity, even at concentrations
up to 100 µM, suggesting that this moiety is not a good
replacement for the pyrrole linker found in the natural
product, coumermycin A1. In contrast, both the monomers
and the dimers containing the olefinic linkers proved to be
active in our assays as shown in Table 1. The optimal tether
length identified from these studies consisted of eight
carbons, 24.
Table 1. Antiproliferative and Her2 Induced Degradation
Activities of Coumermycin A1 Analogues Reported in µM
(n ) 3)
entry (IC50)
MCF-7
>100
SkBr3
>100
Her2 ELISA
9
1
1
1
1
1
2
2
2
2
>100
0
>100
>100
>100
>100
MCF-7 breast cancer cells. The IC50 values obtained for these
compounds were 16.2, 2.7, and 23.9 µM, respectively, clearly
indicating that the geometry of the tether is important for
inhibitory activity (Table 2). Interestingly, the more flexible
5a
6a
7a
8a
3
4
5
6
26.6 ( 0.7
6.7 ( 0.5
6.2 ( 0.5
15.6 ( 1.5
53.1 ( 7.1
3.9 ( 0.7
13.7 ( 3.1
67.4 ( 5.1
352 ( 54
5.0 ( 0.1
34.9 ( 11.0
5.5 ( 1.5
8.4 ( 1.8
28.1 ( 4.6
>100
1.5 ( 0.1
16.7 ( 7.2
>100
5.0 ( 0.4
11.9 ( 1.9
10.3 ( 2.9
82.9 ( 4.3
5.6 ( 1.3
9.6 ( 2.4
10.5 ( 0.3
357 ( 3.0
1.6 ( 1.2
Table 2. Antiproliferative and Her2 Induced Degradation
Activities of Coumermycin A1 Analogues Reported in µM
novobiocin
coumermycin A1
464 ( 2
8.8 ( 0.1
(n ) 3)
entry (IC50)
MCF-7
SkBr3
Her2 ELISA
3
33
35
4
4
1
16.2 ( 0.2
2.7 ( 1.0
23.9 ( 5.4
56.6 ( 5.6
81.0 ( 4.1
82.2 ( 0.7
1.9 ( 0.2
27.6 ( 2.9
53.7 ( 4.8
91.9 ( 1.4
95.2 ( 1.6
6.7 ( 1.3
86.9 ( 7.8
9.3 ( 3.6
85.6 ( 5.0
With the optimal chain length in hand, we wished to
examine the effects of olefin geometry on inhibitory activity.
We therefore pursued the synthesis of alkyne diacid 27
1
2
(Scheme 3), which represents a suitable intermediate for
construction of not only the alkyne product, but also the cis
and saturated derivatives.18 Diacid 29 was prepared by
Lindlar reduction, whereas 28 was furnished by hydrogena-
tion of 27. The resulting acids were coupled with 6 following
our previously described protocol, enlisting EDCI and
pyridine to afford 30, 32, and 34. The cyclic carbonates were
treated with methanolic triethylamine to furnish diols 31, 33,
and 35 for biological evaluation.
derivative 33 proved to be most active. The saturated
derivative (33) was approximately 2-fold more active than
the trans isomer, and we proposed that this hydrophobic
linker may actually be solvent exposed upon binding to
Hsp90. Therefore, we postulated that a triazole linker, which
mimicked the trans geometry of 24, could provide additional
solubilization and hydrogen-bonding interactions and may
lead to increased inhibitory activity. To this end, we prepared
the related triazoles via coupling of 6 with the requisite azides
and alkyne, respectively (Scheme 4). Following the procedure
Upon completion of their syntheses, compounds 31, 33,
and 35 were evaluated for antiproliferative activity against
(
15) Connon, S. J.; Blechirt, S. Angew. Chem., Int. Ed. 2003, 42, 1900-
1
9
1
4
1
923.
(
of Sharpless and co-workers, azides 38 and 39 underwent
smooth cyclization with alkyne 36 to afford the triazole
16) (a) Clevenger, R. C.; Blagg, B. S. J. Org. Lett. 2004, 6, 4459-
462. (b) Shen, G.; Blagg, B. S. J. Org. Lett. 2005, 7, 2157-2160.
(17) Huezo, H.; Vilenchik, M.; Rosen, N.; Chiosis, G. Chem. Biol. 2003,
0, 629-637.
(
(19) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004-2021.
18) Johnson, A. W. J. Chem. Soc. 1946, 1009-1015.
Org. Lett., Vol. 8, No. 21, 2006
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