Integrin-Targeting Devices
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 23 5639
CH2Cl2-MeOH, followed by prep-TLC (CH2Cl2-MeOH). 1H
NMR (400 MHz, CDCl3/CD3OD): δ 7.92 (1H, d, J ) 4.7 Hz),
7.57 (1H, ddd, J ) 8.8, 7.4, 1.8 Hz), 7.01 (1H, d, J ) 8.5 Hz),
6.78 (1H, dd, J ) 8.2, 2.6 Hz), 6.77 (1H, d, J ) 2.4 Hz), 6.62
(2H, t, J ) 8.5 Hz), 5.25 (1H, d, J ) 16.7 Hz), 4.50 (2H, m),
4.30 (2H, m), 4.06 (2H, m), 3.64-3.59 (4H, m), 3.53-3.46 (6H,
m), 3.67 (4H, m), 3.26 (4H, t, J ) 6.8 Hz), 3.01-2.71 (4H, m),
2.39 (1H, dd, J ) 16.1, 4.1 Hz), 2.30 (2H, t, J ) 7.1 Hz), 2.16
(4H, m), 1.79-1.56 (10H, m), 1.53-1.38 (4H, m). MS (ESI),
m/z: 800.6 (MH+), 822.6 (MNa+).
General Method for the Syntheses of the Antagonist
Diketones (17-23) from Their Precursors (24-30). The
precursors 24-30 (0.1 mmol) were stirred with TFA (0.5 mL)
and anisole (0.5 mL) for 16 h at 0 °C. Solvents were removed
under vacuum, and the crude products were treated with 1a
(0.11 mmol) in CH3CN for 2-5 h. It was then worked up using
aqueous (10%) citric acid solution and CH2Cl2. Solvents were
removed under vacuum, and the residues were purified over
silica gel (CH2Cl2-MeOH, 1:0-3:1), affording pure 17-23 in
31-74% yields.
d, J ) 7.4 Hz), 7.62 (2H, d, J ) 8.1 Hz), 7.45 (2H, d, J ) 7.7
Hz), 7.37 (2H, d, J ) 7.0 Hz), 7.32 (2H, m), 7.25 (2H, d, J )
8.1 Hz), 7.12 (2H, d, J ) 8.4 Hz), 6.39 (1H, d, J ) 7.3 Hz),
6.33 (1H, d, J ) 8.4 Hz), 4.65 (1H, dd, J ) 9.6, 4.4 Hz), 4.12
(1H, m), 3.90 (1H, m), 3.69 (2H, m), 3.60-3.45 (8H, m), 3.10
(2H, m), 3.04 (2H, t, J ) 7.0 Hz), 2.91 (2H, m), 2.88 (3H, s),
2.85 (2H, m), 2.55 (1H, s), 2.42 (1H, m), 2.36 (2H, t, J ) 7.3
Hz), 2.22 (2H, t, J ) 7.7 Hz), 2.15 (1H, m), 1.98 (3H, s), 1.94
(2H, m), 1.55 (2H, m). MS (ESI), m/z: 929 (MH+), 951 (MNa+),
927 (M - H)-. HRMS (ESI-TOF high acc) calcd for C48H61-
N6O11S 929.4113 (MH+), found 929.4107.
Compound 21. The crude product obtained from the
reaction of 28 (62 mg, 0.08 mmol) with TFA (0.5 mL) in the
presence of anisole (0.5 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (38 mg, 0.09 mmol) and Et3N (0.14 mL) in CH3-
CN (2 mL) to afford pure 21 (50 mg, 68%). Rf ) 0.8 (CH2Cl2-
1
MeOH, 7:3). H NMR (600 MHz, CD3OD/CDCl3): δ 7.73 (2H,
d, J ) 8.3 Hz), 7.68 (2H, d, J ) 8.3 Hz), 7.54 (1H, t, J ) 8.3
Hz), 7.43 (2H, m), 7.22 (2H, dd, J ) 7.9, 5.3 Hz), 7.10 (2H, m),
6.53 (1H, d, J ) 8.8 Hz), 6.47 (1H, d, J ) 7.4 Hz), 3.83 (1H,
dd, J ) 7.4, 4.8 Hz), 3.68 (1H, dd, J ) 13.6, 5.3 Hz), 3.63 (1H,
dd, J ) 13.6, 7.5 Hz), 3.58 (2H, m), 3.53 (4H, m), 3.40 (2H, t,
J ) 6.6 Hz), 3.36 (2H, t, J ) 5.3 Hz), 3.31 (2H, m), 2.99 (2H,
m), 2.93 (2H, m), 2.89 (3H, s), 2.85 (2H, t, J ) 7.9 Hz), 2.80
(1H, s), 2.64 (2H, t, J ) 7.4 Hz), 2.55 (2H, t, J ) 7.9 Hz), 2.36
(2H, t, J ) 7.4 Hz), 2.26 (2H, t, J ) 7.4 Hz), 2.14 (1H, s), 1.99
(3H, s), 1.95 (2H, q, J ) 7.0 Hz), 1.79 (2H, m). MS (ESI), m/z:
929 (MH+), 927 (M - H)-. HRMS (ESI-TOF high acc) calcd
for C48H61N6O11S 929.4113 (MH+), found 929.4120.
Compound 17. The crude product obtained from the
reaction of 24 (73 mg, 0.08 mmol) with TFA (0.5 mL) in the
presence of anisole (0.5 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (38 mg, 0.09 mmol) and Et3N (0.14 mL) in CH3-
CN (2 mL) to afford pure 17 (52 mg, 64%). Rf ) 0.5 (CH2Cl2-
1
MeOH, 4:1). H NMR (600 MHz, CD3OD/CDCl3): δ 7.78 (1H,
d, J ) 8.3 Hz), 7.61 (1H, m), 7.43 (2H, m), 7.10 (2H, m), 6.89
(2H, s), 6.76 (2H, m), 6.57 (1H, d, J ) 8.8 Hz), 6.50 (1H, d, J
) 7.0 Hz), 4.29 (1H, m), 4.20 (1H, m), 4.02 (2H, m), 3.98 (1H,
m), 3.82 (1H, m), 3.76 (1H, m), 3.70 (2H, m), 3.64 (2H, t, J )
4.4 Hz), 3.52 (2H, t, J ) 6.2 Hz), 3.35 (2H, m), 3.23 (2H, t, J
) 6.5 Hz), 2.90 (3H, s), 2.91-2.81 (6H, m), 2.64 (6H, s), 2.55
(2H, t, J ) 7.4 Hz), 2.35 (2H, t, J ) 7.9 Hz), 2.22 (2H, t, J )
7.0 Hz), 2.20 (3H, s), 2.01 (3H, s), 1.93 (2H, m), 1.73 (2H, m).
MS (ESI), m/z: 987 (MH+), 1009 (MNa+), 1025 (MK+), 985 (M
- H)-. HRMS (ESI-TOF high acc) calcd for C51H67N6O12S
987.4532 (MH+), found 987.4527.
Compound 22. The crude product obtained from the
reaction of 29 (138 mg, 0.17 mmol) with TFA (1 mL) in the
presence of anisole (1 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (78 mg, 0.19 mmol) and Et3N (0.15 mL) in CH3-
CN (2 mL) to afford pure 22 (82 mg, 51%). Rf ) 0.3 (CH2Cl2-
1
MeOH, 4:1). H NMR (500 MHz, CD3OD/CDCl3): δ 7.66 (2H,
d, J ) 8.1 Hz), 7.52 (1H, t, J ) 7.7 Hz), 7.43 (2H, d, J ) 8.4
Hz), 7.21 (2H, d, J ) 8.4 Hz), 7.11 (2H, d, J ) 8.4 Hz), 6.85
(2H, s), 6.60 (1H, d, J ) 8.8 Hz), 6.47 (1H, d, J ) 7.0 Hz), 3.74
(1H, m), 3.68 (1H, m), 3.67 (2H, t, J ) 5.1 Hz), 3.62 (3H, m),
3.55 (2H, m), 3.47 (4H, m), 3.23 (2H, t, J ) 7.0 Hz), 3.00 (2H,
m), 2.94 (2H, m), 2.85 (2H, t, J ) 7.4 Hz), 2.81 (1H, s), 2.60
(6H, s), 2.55 (2H, t, J ) 7.4 Hz), 2.36 (2H, t, J ) 7.4 Hz), 2.24
(2H, t, J ) 7.3 Hz), 2.17 (3H, s), 1.99 (3H, s), 1.95 (2H, q, J )
7.7 Hz), 1.72 (2H, q, J ) 6.3 Hz). MS (ESI), m/z: 957 (MH+),
979 (MNa+), 995 (MK+), 955 (M - H)-. HRMS (ESI-TOF high
acc) calcd for C50H65N6O11S 957.4426 (MH+), found 957.4436.
Compound 18. The crude product obtained from the
reaction of 25 (62 mg, 0.08 mmol) with TFA (0.5 mL) in the
presence of anisole (0.5 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (38 mg, 0.09 mmol) and Et3N (0.14 mL) in CH3-
CN (2 mL) to afford pure 18 (46 mg, 62%). 1H NMR (500 MHz,
CD3OD/CDCl3): δ 9.00 (1H, s), 8.44 (1H, d, J ) 7.3 Hz), 7.69
(1H, d, J ) 8.1 Hz), 7.51 (3H, m), 7.05 (2H, d, J ) 8.5 Hz),
6.92 (2H, s), 6.85 (1H, s), 6.47 (1H, s), 6.41 (1H, d, J ) 8.8
Hz), 6.37 (2H, m), 6.22 (1H, d, J ) 6.6 Hz), 5.46 (1H, s), 4.55
(1H, s), 4.11 (1H, s), 3.86 (1H, m), 3.64 (1H, m), 3.53 (1H, s),
3.37 (1H, m), 3.23 (1H, m), 2.90-2.75 (10H, m), 2.65 (6H, s),
2.53 (2H, t, J ) 8.1 Hz), 2.32 (2H, m), 2.28 (3H, s), 2.21 (2H,
m), 2.03 (3H, s), 1.96 (4H, m), 1.62 (4H, m). MS (ESI), m/z:
928 (MH+), 950 (MNa+), 926 (M - H)-.
Compound 23. The crude product obtained from the
reaction of 30 (73 mg, 0.08 mmol) with TFA (0.5 mL) in the
presence of anisole (0.5 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (37 mg, 0.09 mmol) and Et3N (80 µL) in CH3CN
(2 mL) to afford pure 23 (60 mg, 74%). Rf ) 0.55 (CH2Cl2-
Compound 19. The crude product obtained from the
reaction of 26 (93 mg, 0.1 mmol) with TFA (0.5 mL) in the
presence of anisole (0.5 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (46 mg, 0.11 mmol) and Et3N (0.14 mL) in CH3-
CN (2 mL) to afford pure 19 (45 mg, 43%). Rf ) 0.45 (CH2-
1
MeOH, 4:1). H NMR (600 MHz, CD3OD/CDCl3): δ 7.65 (2H,
d, J ) 8.3 Hz), 7.54 (1H, t, J ) 7.9 Hz), 7.44 (2H, m), 7.20
(2H, d, J ) 8.3 Hz), 7.12 (2H, m), 6.86 (2H, s), 6.59 (1H, d, J
) 8.8 Hz), 6.46 (1H, d, J ) 6.6 Hz), 3.73 (1H, dd, J ) 7.0, 5.3
Hz), 3.67-3.62 (6H, m), 3.56 (6H, m), 3.48 (2H, t, J ) 6.1 Hz),
3.38 (2H, t, J ) 7.0 Hz), 3.32 (2H, m), 3.24 (2H, t, J ) 7.0 Hz),
2.99 (2H, m), 2.93 (2H, m), 2.85 (2H, t, J ) 7.4 Hz), 2.61 (6H,
s), 2.56 (2H, t, J ) 7.9 Hz), 2.37 (2H, t, J ) 7.4 Hz), 2.24 (2H,
t, J ) 7.4 Hz), 2.18 (3H, s), 2.00 (3H, s), 1.94 (2H, m), 1.88
(2H, m), 1.72 (2H, m). MS (ESI), m/z: 1015 (MH+), 1037
(MNa+), 1013 (M - H)-. HRMS (ESI-TOF high acc) calcd for
C53H71N6O12S 1015.4845 (MH+), found 1015.4853.
1
Cl2-MeOH, 4:1). H NMR (500 MHz, CD3OD/CDCl3): δ 7.76
(1H, d, J ) 8.1 Hz), 7.67 (1H, t, J ) 8.4 Hz), 7.45 (2H, m),
7.11 (2H, m), 6.96 (2H, s), 6.71 (2H, m), 6.65 (1H, d, J ) 9.2
Hz), 6.52 (1H, d, J ) 7.0 Hz), 4.19 (2H, m), 4.09 (1H, m), 3.76
(1H, dq, J ) 9.2, 4.4 Hz), 3.72 (1H, s), 3.67 (1H, t, J ) 4.1 Hz),
3.30 (2H, m), 3.20 (2H, t, J ) 7.0 Hz), 3.01 (2H, m), 2.99 (3H,
s), 2.93 (5H, m), 2.73 (6H, s), 2.62 (2H, t, J ) 7.7 Hz), 2.44
(2H, t, J ) 7.7 Hz), 2.31 (2H, m), 2.30 (3H, s), 2.25 (2H, t, J )
7.4 Hz), 2.07 (3H, s), 2.04 (4H, m), 1.67 (6H, m), 1.56 (2H, m),
1.38 (2H, m). MS (ESI), m/z: 1041 (MH+), 1063 (MNa+), 1039
(M - H)-; HRMS (ESI-TOF high acc) calcd for C55H74N7O11S
1040.5161 (MH+), found 1040.5164.
Acknowledgment. This study was supported by the
Skaggs Institute for Chemical Biology.
Supporting Information Available: List of physical data
of selected compounds, figures showing the binding modes of
compounds 72 and 76, and grid of the X-ray structure of
integrin Rvâ3 used for the AutoDock calculation. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Compound 20. The crude product obtained from the
reaction of 27 (50 mg, 0.064 mmol) with TFA (0.5 mL) in the
presence of anisole (0.5 mL) in CH2Cl2 (2 mL) was reacted with
compound 1a (30 mg, 0.07 mmol) and Et3N (70 µL) in CH3CN
(2 mL) to afford pure 20 (35 mg, 59%). Rf ) 0.45 (CH2Cl2-
1
MeOH, 4:1). H NMR (500 MHz, CD3OD/CDCl3): δ 7.79 (2H,