G. Chiosis et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3529–3532
3531
9. GM-4-GM: A solution of GM (28 mg, 0.05 mmol) and
1,4-diaminobutane (2.2 mg, 0.025 mmol) in dry DMF
(0.5 mL) was stirred for 1 h at room temperature (rt)
under inert atmosphere. The solvent was quickly removed
under high vacuum, and the mixture applied to a silica gel
column. CH2Cl2/acetone (4:1) was first applied to remove
any unreacted GM (yellow), followed by CH2Cl2/acetone
(2:1) to afford GM-4-GM (27.0 mg, 90%) as a purple solid.
Rf (CH2Cl2/acetone 3:1) 0.1; 1H NMR (400 MHz, CDCl3):
d 9.16 (s, 2H), 7.25 (s, 2H), 6.95 (d, J = 11 Hz, 2H), 6.58
(dd, J = 11 Hz, 2H), 6.27 (m, 2H), 5.89–5.84 (m, 4H), 5.18
(s, 2H), 4.96 (br s, 4H), 4.31 (d, J = 10 Hz, 2H), 4.16 (br s,
2H), 3.59–3.44 (m, 8H), 3.36 (s, 6H), 3.27 (s, 6H),
2.76–2.68 (m, 4H), 2.37 (t, J = 11 Hz, 4H), 2.03 (s, 6H),
1.79–1.64 (m, 16H), 1.00–0.96 (m, 12H). MS m/z
GM-4-GM
GM-4C-GM
GM-4T-GM
GM-9-GM
GM
100
75
50
25
0
17AAG
0
1
2
3
4
log 10 [inhibitor] (nM)
Figure 3. Competitive binding of synthesized dimers to Hsp90 alpha.
1167.6 (M+Na). GM-9-GM:
A
solution of GM
dimerization and also to determine subunit inter-
face(s) in Hsp90.
(21 mg, 0.037 mmol) and 1,9-diaminononane (2.9 mg,
0.018 mmol) in dry DMF (0.5 mL) was stirred for 0.5 h
at rt under inert atmosphere. The solvent was quickly
removed under high vacuum, and the mixture applied to a
silica gel column. CH2Cl2/acetone (4:1) was first applied to
remove any unreacted GM (yellow), followed by CH2Cl2/
acetone (2:1) to afford GM-9-GM (20.0 mg, 91%) as a
purple solid. Rf (CH2Cl2/acetone 3:1) 0.15; 1H NMR
(400 MHz, CDCl3): d 9.18 (s, 2H), 7.27 (s, 2H), 6.95 (d,
J = 11 Hz, 2H), 6.57 (dd, J = 11 Hz, 2H), 6.28 (m, 2H),
5.91–5.82 (m, 4H), 5.18 (s, 2H), 4.76 (br s, 4H), 4.34-4.28
(m, 4H), 3.58–3.40 (m, 8H), 3.35 (s, 6H), 3.26 (s, 6H),
2.75–2.60 (m, 4H), 2.41 (t, J = 11 Hz, 2H), 2.01 (s, 6H),
1.84 (s, 6H), 1.70–1.63 (m, 4H), 1.40–1.29 (m, 8H), 1.00–
0.95 (m, 12H). MS m/z 1215.9 (M+H). GM-4C-GM: A
solution of GM (11.8 mg, 0.021 mmol), (Z)-1,4-diamino-
2-butene, HCl salt (1.4 mg, 0.009 mmol), and 0.03 mL
N,N-diisopropylethylamine (DIEA) in dry DMF
(0.25 mL) was stirred for 2 h at rt under inert atmosphere.
The solvent was quickly removed under high vacuum, and
the mixture applied to a silica gel column. CH2Cl2/acetone
(4:1) was first applied to remove any unreacted GM
(yellow), followed by CH2Cl2/acetone (2:1) to afford
Acknowledgments
This work was supported by grants from the Susan
G. Komen Breast Cancer Foundation, Mr. William H.
Goodwin and Mrs. Alice Goodwin, the Commonwealth
Cancer Foundation for Research, the Experimental
Therapeutics Center of Memorial Sloan-Kettering
Cancer Center (GC and JA), and the NIH
(DK053058)(CVN).
Supplementary data
Supplementary data associated with this article can be
GM-4C-GM (7.4 mg, 75%) as
a
purple solid. 1H
References and notes
NMR (400 MHz, CDCl3): d 9.13 (s, 2H), 7.30 (s, 2H),
6.95 (d, J = 11 Hz, 2H), 6.58 (dd, J = 11 Hz, 2H), 6.16
(m, 2H), 5.89–5.80 (m, 6H), 5.20 (s, 2H), 4.78 (br s, 4H),
4.34–4.14 (m, 6H), 3.58–3.40 (m, 4H), 3.36 (s, 6H), 3.28
(s, 6H), 2.75–2.63 (m, 4H), 2.35 (t, J = 11 Hz, 2H), 2.03
(s, 6H), 1.85(s, 6H), 1.85–1.67 (m, 6H), 1.00–0.95
(m, 12H). MS m/z 1165.7 (M+Na). GM-4T-GM: A
solution of Boc-protected (E)-1,4-diamino-2-butene
(2.2 mg, 0.0077 mmol) in 1 mL CH2Cl2/TFA (4:1) with
added 10% thioanisole was stirred for 1 h at rt. Solvent
was speedily removed, and GM (9.2 mg, 0.016 mmol)
dissolved in dry DMF (0.6 mL) containing 0.02 mL DIEA
was added to the crude material. The resulting solution
was stirred for 24 h at rt under inert atmosphere. The
solvent was quickly removed under high vacuum, and the
mixture applied to a silica gel column. CH2Cl2/acetone
(5:1) was first applied to remove any unreacted GM
(yellow), followed by CH2Cl2/acetone (1:1) to afford GM-
4T-GM (6.4 mg, 75%) as a purple solid. 1H NMR
(400 MHz, CDCl3): d 9.10 (s, 2H), 7.26 (s, 2H), 6.91 (d,
J = 11 Hz, 2H), 6.54 (dd, J = 11 Hz, 2H), 6.30 (m, 2H),
5.86–5.72 (m, 6H), 5.15 (s, 2H), 4.75 (br s, 4H), 4.26 (d,
J = 10 Hz, 2H), 4.15–3.04 (m, 4H), 4.01 (br s, 2H), 3.52–
3.38 (m, 4H), 3.31 (s, 6H), 3.22 (s, 6H), 2.71–2.58 (m, 4H),
2.25 (t, J = 11 Hz, 2H), 1.97 (s, 6H), 1.75 (s, 6H), 1.75–1.60
(m, 6H), 0.95–0.92 (m, 12H). MS m/z 1165.7 (M+Na).
GM-4Y-GM: A solution of Boc-protected 1,4-diamino-2-
butyne (1.1 mg, 0.0039 mmol) in 1 mL CH2Cl2/TFA (4:1)
with added 10% thioanisole was stirred for 1 h at rt.
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