Journal of Medicinal Chemistry
Article
μmol). HRMS: m/z calcd for C29H40BrN9O7 + H+ [M + H]+
706.2306. Found: 706.2311.
c(RGDW(7Br)(NMe)v) (20). Compound 20 was obtained as a
=
c(RGDw(7I)V) (23). Compound 23 was obtained as a colorless TFA
solid (19.9 mg, 23 μmol, 21%, (overall: 18%), scale: 109 μmol).
HRMS: m/z calcd for C28H38IN9O7 + H+ [M + H]+ = 740.2011.
Found: 740.1990. 1H NMR (600 MHz, 333 K, DMSO-d6) δ = 11.97
(s, 1H, D-COOH), 10.60 (d, 1H, J = 2.6 Hz, Ind-NH), 8.21 (dd, 1H,
J = 7.7, 4.2 Hz, G-NαH), 8.03 (d, 1H, J = 8.5 Hz, D-NαH), 7.86 (d,
1H, J = 7.4 Hz, w-NαH), 7.76 (d, 1H, J = 7.8 Hz, V-NαH), 7.67 (d,
1H, J = 8.0 Hz, R-NαH), 7.60−7.52 (m, 2H, guanidinium-NH, Ind-
H), 7.46 (d, 1H, J = 7.4 Hz, Ind-H), 7.13 (d, 1H, J = 2.4 Hz, Ind-H2),
colorless TFA solid (9.4 mg, 11 μmol, 35% (overall: 8%), scale: 32
μmol). HRMS: m/z calcd for C29H40BrN9O7 + H+ [M + H]+
=
706.2306. Found: 706.2308. 1H NMR (600 MHz, 298 K, DMSO-d6)
δ = 12.37 (s, 1H, D-COOH), 11.10 (d, 1H, J = 2.5 Hz, Ind-NH), 9.01
(d, 1H, J = 7.2 Hz, 1H, D-CαNH), 8.49 (dd, 1H, J = 8.3, 4.1 Hz, G-
CαNH), 7.54 (d, 1H, J = 7.9 Hz, Ind-H4), 7.52−7.46 (m, 1H,
guanidinium-NH), 7.28 (d, 1H, J = 7.5 Hz, Ind-H6), 7.19 (d, 1H, J =
2.5 Hz, Ind-H2), 7.14 (d, 1H, J = 8.9 Hz, R-CαNH), 7.05 (d, 1H, J =
9.0 Hz, W-CαNH), 6.93 (t, 1H, J = 7.7 Hz, Ind-H5), 4.72 (ddd, 1H, J
= 8.6, 8.6, 4.5 Hz, W-CαH), 4.62 (ddd, 1H, J = 8.9, 8.9, 7.0 Hz, R-
CαH), 4.44 (d, 1H, J = 11.2 Hz, v-CαH), 4.21−4.13 (m, 2H, D-CαH,
G-CαH1), 3.23 (dd, 1H, J = 16.5, 4.1 Hz, G-CαH2), 3.12−3.03 (m,
3H, R-CδH, W-CβH1), 2.92−2.85 (m, 2H, D-CβH1,W-CβH2), 2.61 (s,
3H, v-NαCH3), 2.47 (dd, 1H, J = 16.5, 7.0 Hz, D-CβH2), 2.10−1.99
(m, 1H, v-CβH), 1.70−1.66 (m, 1H, R-CβH1), 1.49−1.42 (m, 1H, R-
CβH2), 1.42−1.31 (m, 2H, R-CγH), 0.70 (d, 3H, J = 2.3 Hz, v-CH3),
0.69 (d, 3H, J = 2.6 Hz, v-CH3). 13C NMR (151 MHz, 298 K,
DMSO-d6) δ = 172.8, 172.5, 171.5, 170.1, 169.4, 168.8, 157.1, 134.7,
129.7, 125.3, 123.9, 120.1, 118.4, 111.4, 104.5, 62.3, 53.0, 51.0, 49.0,
42.9, 40.9, 35.3, 29.6, 29.5, 29.1, 25.4, 24.3, 19.7, 18.5.
+
7.10−6.94 (bs, 3H, guanidinium-NH3 ), 6.81 (t, 1H, J = 7.6 Hz, Ind-
H5), 4.66 (ddd, 1H, J = 8.3, 8.3, 5.6 Hz, D-CαH), 4.58 (ddd, 1H, J =
7.7, 7.7, 5.6 Hz, w-CαH), 4.16 (ddd, 1H, J = 7.8, 7.8, 5.6 Hz, R-CαH),
4.06 (dd, 1H, J = 15.1, 7.7 Hz, G-CαH1), 3.76 (t, 1H, J = 7.5 Hz, V-
CαH), 3.27 (dd, 1H, J = 15.1, 4.2 Hz, G-CαH2), 3.18 (bs, 1H), 3.14−
3.05 (m, 3H, R-CδH, w-CβH1), 2.94 (dd, 1H, J = 14.3, 5.6 Hz, w-
CβH2), 2.76 (dd, 1H, J = 16.3, 8.2 Hz, D-CβH1), 2.44 (dd, 1H, J =
16.3, 5.6 Hz, D-CβH2), 1.84−1.79 (m, 1H, V-CβH), 1.78−1.73 (m,
1H, R-CβH2), 1.56−1.38 (m, 3H, R-CγH, R-CβH1), 0.73 (d, 3H, J =
6.8 Hz, V-CH3), 0.64 (d, 3H, J = 6.7 Hz, 3H, V-CH3). 13C NMR (151
MHz, 333 K, DMSO-d6) δ = 172.1, 171.6, 171.6, 171.5, 170.4, 169.8,
157.3, 138.3, 130.2, 128.5, 124.9, 120.6, 119.0, 112.0, 76.9, 61.0, 54.1,
52.5, 49.5, 43.7, 40.9, 35.5, 29.8, 28.8, 28.0, 25.8, 19.5, 18.7.
c(RGDw(6Br)V) (24). Compound 24 was obtained as a colorless
TFA solid (5.3 mg, 6.6 μmol, 24%, (overall: 4%), scale: 28 μmol).
HRMS: m/z calcd for C28H38BrN9O7 + H+ [M + H]+ = 692.2150.
Found: 962.2145. 1H NMR (500 MHz, 298 K, DMSO-d6) δ = 12.27
(s, 1H, D-COOH), 10.97 (d, 1H, J = 2.4 Hz, Ind-NH), 8.41 (dd, 1H,
J = 7.6, 4.3 Hz, G-NαH), 8.25 (d, 1H, J = 8.5 Hz, D-NαH), 7.92 (d,
1H, J = 7.1 Hz, w-NαH), 7.87 (d, 1H, J = 7.6 Hz, V-NαH), 7.70 (d,
1H, J = 8.2 Hz, R-NαH), 7.53 (t, 1H, J = 5.9 Hz, guanidinium-NH),
7.51−7.47 (m, 2H, Ind-H4, Ind-H7), 7.12−7.07 (m, 2H, Ind-H2, Ind-
H5), 4.66 (ddd, 1H, J = 8.7, 8.7, 5.7 Hz, D-CαH), 4.51 (ddd, 1H, J =
8.0, 8.0, 5.7 Hz, w-CαH), 4.15 (ddd, 1H, J = 8.1, 8.1, 5.6 Hz, R-CαH),
4.02 (dd, 1H, J = 15.1, 7.6 Hz, G-CαH1), 3.71 (t, 1H, J = 7.5 Hz, V-
CαH), 3.27 (dd, 1H, J = 15.1, 4.3 Hz, G-CαH2), 3.13−2.99 (m, 3H, R-
CδH, w-CβH1), 2.93 (dd, 1H, J = 14.2, 5.3 Hz, w-CβH2), 2.79 (dd, 1H,
J = 16.4, 8.8 Hz, D-CβH1), 2.41 (dd, 1H, J = 16.4, 5.6 Hz, D-CβH2),
1.82−1.75 (m, 1H, V-CβH), 1.73−1.67 (m, 1H, R-CβH1), 1.53−1.33
(m, 3H, R-CγH, R-CβH2), 0.71 (d, 3H, J = 6.8 Hz, V-CH3), 0.60 (d,
3H, J = 6.6 Hz, V-CH3). 13C NMR (151 MHz, 298 K, DMSO-d6) δ =
171.7, 171.2, 171.1, 170.9, 169.9, 169.6, 156.6, 136.8, 126.4, 124.5,
121.0, 120.1, 118.1, 116.1, 110.1, 60.6, 53.8, 51.9, 48.8, 43.1, 40.2,
34.6, 29.3, 28.5, 27.4, 25.3, 19.1, 18.3.
c(RGDw(7F)V) (21). Compound 21 was obtained as a colorless
TFA solid (29.8 mg, 40 μmol, 42% (overall: 26%) scale: 95 μmol).
HRMS: m/z calcd for C28H38FN9O7 + H+ [M + H]+ = 632.2951.
Found: 632.2956. 1H NMR (600 MHz, 333 K, DMSO-d6) δ = 12.10
(s, 1H, D-COOH), 11.16 (d, 1H, J = 2.5 Hz, Ind-NH), 8.22 (dd, 1H,
J = 7.5, 4.2 Hz, G-NαH), 8.03 (d, 1H, J = 8.5 Hz, D-NαH), 7.87 (d,
1H, J = 8.0 Hz, w-NαH), 7.77 (d, 1H, J = 7.8 Hz, V-NαH), 7.65 (d,
1H, J = 8.0 Hz, R-NαH), 7.58 (t, 1H, J = 5.9 Hz, guanidinium-NH),
7.36 (d, 1H, J = 7.9 Hz, Ind-H4), 7.12 (d, 1H, J = 2.4 Hz, Ind-H2),
7.06 (bs, 2H, guanidinium-NH2), 6.94 (td, 1H, J = 7.8, 4.7 Hz, Ind-
H5), 6.86 (dd, 1H, J = 11.6, 7.7 Hz, Ind-H6), 4.68 (ddd, 1H, J = 8.5,
8.5, 5.7 Hz, D-CαH), 4.58 (ddd, 1H, J = 8.0, 8.0, 5.6 Hz, w-CαH), 4.15
(ddd, 1H, J = 8.0, 8.0, 5.8 Hz, R-CαH), 4.05 (dd, 1H, J = 15.0, 7.5 Hz,
G-CαH1), 3.76 (t, 1H, J = 7.5 Hz, V-CαH), 3.27 (dd, 1H, J = 15.0, 4.2
Hz, G-CαH2), 3.14−3.07 (m, 3H, R-CδH, w-CβH1), 2.97 (dd, 1H, J =
14.3, 5.6 Hz, w-CβH2), 2.78 (dd, 1H, J = 16.3, 8.4 Hz, D-CβH1), 2.42
(dd, 1H, J = 16.3, 5.7 Hz, D-CβH2), 1.87−1.71 (m, 2H, V-CβH, R-
CβH1), 1.56−1.38 (m, 3H, R-CγH, R-CβH2), 0.73 (d, 3H, J = 6.8 Hz,
V-CH3), 0.64 (d, 3H, J = 6.7 Hz, V-CH3). 13C NMR (151 MHz, 333
K, DMSO-d6) δ = 172.0, 171.6, 171.6, 171.5, 170.4, 169.9, 157.4,
149.7 (d, J = 242.5 Hz), 132.0 (d, J = 5.9 Hz), 125.0, 124.3 (d, J =
13.2 Hz), 118.9 (d, J = 6.3 Hz), 115.0 (d, J = 2.7 Hz), 111.5, 106.0 (d,
J = 16.1 Hz), 61.0, 54.2, 52.6, 49.5, 43.7, 40.8, 40.7, 35.3, 29.8, 28.9,
27.9, 25.8. 19F NMR (565 MHz, 333 K, DMSO-d6) δ = −134.2 (dd, J
= 11.6, 4.7 Hz)
c(RGDw(6Cl)V) (25). Compound 25 was obtained as a colorless
TFA solid (7.0 mg, 9.2 μmol, 34%, (overall: 6%), scale: 27 μmol).
HRMS: m/z calcd for C28H38ClN9O7 + H+ [M + H]+ = 648.2655.
Found: 648.2681. 1H NMR (600 MHz, 298 K, DMSO-d6) δ = 12.28
(s, 1H, D-COOH), 10.96 (d, 1H, J = 1.8 Hz, Ind-NH), 8.41 (dd, 1H,
J = 7.5, 4.4 Hz, G-NαH), 8.21 (d, 1H, J = 8.4 Hz, D-NαH), 7.91 (d,
1H, J = 7.1 Hz, w-NαH), 7.82 (d, 1H, J = 7.6 Hz, V-NαH), 7.60 (d,
1H, J = 8.1 Hz, R-NαH), 7.53−7.49 (m, 2H, guanidinium-NH, Ind-
H4), 7.34 (d, 1H, J = 1.9 Hz, Ind-H7), 7.11 (d, 1H, J = 2.3 Hz, Ind-
H2), 6.99 (dd, 1H, J = 8.4, 1.9 Hz, Ind-H5), 4.65 (ddd, 1H, J = 8.7,
8.7, 5.6 Hz, D-CαH), 4.51 (ddd, 1H, J = 7.1, 7.1, 5.2 Hz, w-CαH), 4.13
(ddd, 1H, J = 8.1, 8.1, 5.9 Hz, R-CαH), 4.01 (dd, 1H, J = 15.0, 7.5 Hz,
G-CαH1), 3.69 (t, 1H, J = 7.4 Hz, V-CαH), 3.26 (dd, 1H, J = 15.0, 4.4
Hz, G-CαH2), 3.13−3.04 (m, 2H, R-CδH), 3.02 (dd, 1H, J = 14.2, 8.5
Hz, w-CβH1), 2.94 (dd, 1H, J = 14.2, 5.2 Hz, w-CβH2), 2.77 (dd, 1H, J
= 16.4, 8.7 Hz, D-CβH1), 2.41 (dd, 1H, J = 16.4, 5.6 Hz, D-CβH2),
1.80−1.74 (m, 1H, V-CβH), 1.71−1.66 (m, 1H, R-CβH1) 1.50−1.31
(m, 3H, R-CγH, R-CβH2), 0.69 (d, 3H, J = 6.7 Hz, V-CH3), 0.59 (d,
3H, J = 6.7 Hz, V-CH3). 13C NMR (151 MHz, 298 K, DMSO-d6) δ =
172.2, 171.7, 171.6, 171.5, 170.3, 170.1, 157.0, 136.8, 126.6, 126.0,
125.1, 120.2, 119.0, 111.2, 110.5, 61.0, 54.2, 52.4, 49.3, 43.5, 40.7,
35.0, 29.7, 29.0, 27.9, 25.8, 19.5, 18.7.
c(RGDw(7Cl)V) (22). Compound 22 was obtained as a colorless
TFA solid (7.9 mg, 10 μmol, 16%, (overall: 7%), scale: 0.06 μmol).
HRMS: m/z calcd for C28H38ClN9O7 + H+ [M + H]+ = 648.2655.
Found: 648.2674. 1H NMR (600 MHz, 298 K, DMSO-d6) δ = 12.28
(s, 1H, D-COOH), 11.17 (d, 1H, J = 1.8 Hz, Ind-NH), 8.40 (dd, 1H,
J = 7.5, 4.4 Hz, G-NαH), 8.20 (d, 1H, J = 8.4 Hz, D-NαH), 7.92 (d,
1H, J = 7.1 Hz, w-NαH), 7.83 (d, 1H, J = 7.5 Hz, V-NαH), 7.61 (d,
1H, J = 7.9 Hz, R-NαH), 7.52−7−50 (m, 2H, guanidinium-NH, Ind-
H4), 7.15 (d, 1H, J = 2.5 Hz, Ind-H2), 7.12 (d, 1H, J = 7.6 Hz, Ind-
H6), 6.99 (t, 1H, J = 7.7 Hz, Ind-H5), 4.65 (ddd, 1H, J = 8.8, 8.8, 5.6
Hz, D-CαH), 4.54 (ddd, 1H, J = 7.1, 7.1, 5.3 Hz, w-CαH), 4.13 (ddd,
1H, J = 8.2, 8.2, 5.8 Hz, R-CαH), 4.01 (dd, 1H, J = 15.0, 7.5 Hz, G-
CαH1), 3.68 (t, 1H, J = 7.5 Hz, V-CαH), 3.26 (dd, 1H, J = 15.0, 4.4
Hz, G-CαH2), 3.12−3.02 (m, 3H, R-CδH, w-CβH1), 2.96 (dd, 1H, J =
14.2, 5.3 Hz, w-CβH2), 2.77 (dd, 1H, J = 16.4, 8.8 Hz, D-CβH1), 2.41
(dd, 1H, J = 16.4, 5.6 Hz, D-CβH2), 1.77 (h, 1H, J = 6.8 Hz, V-CβH),
1.72−1.67 (m, 1H, R-CβH1), 1.51−1.32 (m, 3H, R-CγH, R-CβH2),
0.69 (d, 3H, J = 6.7 Hz, V-CH3), 0.59 (d, 3H, J = 6.7 Hz, V-CH3). 13
C
c(RGDwV) (31). Compound 31 was obtained as a colorless TFA
solid (49.4 mg, 68 μmol, 48%, (overall: 34%), scale: 200 μmol).37 LC-
MS: m/z calcd for C28H39N9O7 + H+ [M + H]+ = 614.30. Found:
614.30.
NMR (151 MHz, 298 K, DMSO-d6) δ = 171.7, 171.2, 171.0, 170.9,
169.9, 169.6, 156.5, 132.8, 129.3, 124.8, 120.3, 119.2, 117.4, 115.7,
111.1, 60.6, 53.7, 51.9, 48.8, 43.1, 40.2, 34.6, 29.2, 28.5, 27.5, 25.3,
19.0, 18.2.
595
J. Med. Chem. 2021, 64, 586−601