Journal of Medicinal Chemistry
Article
1
7
5
3
2
1
70.9, 170.7, 170.4, 170.4, 170.0, 154.0, 153.7, 153.4, 116.3, 116.1,
2.8, 72.6, 72.5, 65.9, 64.1, 61.4, 60.8, 60.7, 59.9, 57.9, 57.7, 57.4,
7.0, 54.9, 53.1, 52.9, 52.3, 51.2, 42.1, 41.6, 38.8, 38.3, 35.2, 33.9,
3.1, 32.5, 32.4, 31.7, 31.3, 30.1, 29.7, 29.3, 28.9, 24.6, 24.5, 23.6,
2.8, 22.4, 22.2, 21.4, 20.4, 20.2, 20.0, 19.7, 19.6, 19.1, 19.0, 18.7,
1H), 2.94 (s, 1H), 2.91 (dd, J = 8.83, 11.75 Hz, 1H), 2.62−2.59 (m,
1H), 2.58 (s, 1H), 2.55 (s, 1H), 2.54−2.52 (m, 1H), 2.39−2.37 (m,
1H), 2.08 (s, 1H), 2.07 (s, 1H), 2.04 (s, 1H), 2.01 (d, J = 5.56 Hz,
1H), 1.98−1.96 (m, 1H), 1.96−1.94 (m, 1H), 1.93−1.86 (m, 2H),
1.81−1.77 (m, 1H), 1.77−1.72 (m, 1H), 1.57−1.53 (m, 1H), 1.51−
1.45 (m, 1H), 1.45−1.40 (m, 1H), 1.38−1.32 (m, 2H), 1.29 (d, J =
6.81 Hz, 1H), 1.26 (dd, J = 2.10, 5.61 Hz, 1H), 1.23 (t, J = 3.46 Hz,
1H), 1.19 (d, J = 7.14 Hz, 1H), 1.15 (td, J = 2.60, 6.56 Hz, 1H), 1.07
(t, J = 5.56 Hz, 2H), 1.02 (d, J = 6.94 Hz, 3H), 1.01 (s, 3H), 0.93 (d, J
= 6.65 Hz, 3H), 0.88 (s, 3H), 0.88 (d, J = 7.68 Hz, 3H), 0.87 (d, J =
6.08 Hz, 6H), 0.86 (d, J = 7.06 Hz, 3H), 0.85 (d, J = 6.22 Hz, 1H),
0.83 (d, J = 7.64 Hz, 3H), 0.82 (d, J = 6.18 Hz, 3H), 0.81 (d, J = 6.59
Hz, 6H), 0.79 (s, 3H), 0.78 (s, 3H), 0.74 (d, J = 6.87 Hz, 3H), 0.68
(d, J = 6.84 Hz, 3H), 0.62 (d, J = 6.79 Hz, 3H), 0.57 (d, J = 6.73 Hz,
+
8.6, 18.5, 17.9, 15.7, 14.3. HRMS m/z: 751.4001 [M + H] . HPLC
purity 95.8%, t = 16.0/16.9 min.
r
Δ -[L-Ala(2-furyl)]-lugdunin (29). Yield: 12.3 mg (49%). 1H
3
NMR (600 MHz, DMSO-d ): δ (ppm) 8.63 (d, J = 8.52 Hz, 1H),
6
8
.58 (d, J = 5.25 Hz, 1H), 8.32 (d, J = 8.43 Hz, 1H), 8.23 (d, J = 9.47
Hz, 1H), 8.10 (d, J = 8.36 Hz, 1H), 8.06 (d, J = 9.04 Hz, 1H), 8.01
d, J = 7.76 Hz, 1H), 7.79 (dd, J = 5.07, 9.33 Hz, 2H), 7.75 (d, J =
.26 Hz, 1H), 7.70 (d, J = 9.32 Hz, 1H), 7.48−7.43 (m, 3H), 6.31
dd, J = 5.89, 8.19 Hz, 1H), 6.29 (dd, J = 6.90, 9.13 Hz, 1H), 6.14 (t, J
3.34 Hz, 2H), 4.75 (d, J = 2.20 Hz, 1H), 4.73 (d, J = 2.22 Hz, 1H),
.64−4.58 (m, 1H), 4.57 (d, J = 4.03 Hz, 1H), 4.56 (dd, J = 2.46, 4.03
Hz, 1H), 4.54 (d, J = 4.09 Hz, 1H), 4.51 (d, J = 4.78 Hz, 1H), 4.49
d, J = 4.80 Hz, 1H), 4.47 (d, J = 9.34 Hz, 1H), 4.40 (d, J = 9.04 Hz,
(
9
(
=
1
3
3H). C NMR (150 MHz, DMSO-d ): δ (ppm) 171.6, 171.6, 171.5,
6
4
171.3, 170.9, 170.6, 170.4, 170.2, 169.9, 169.9, 169.8, 169.2, 140.1,
139.1, 126.6, 126.6, 126.5, 126.2, 124.3, 124.1, 76.3, 76.3, 74.6, 74.5,
74.5, 74.5, 74.4, 72.3, 72.1, 72.1, 65.3, 65.2, 64.7, 63.7, 60.6, 59.0,
57.4, 57.3, 57.2, 56.8, 56.6, 54.4, 53.4, 52.3, 50.7, 41.4, 41.1, 38.1,
37.6, 32.6, 32.1, 32.0, 31.1, 30.6, 29.7, 29.3, 29.1, 28.6, 24.1, 24.0,
23.1, 22.4, 22.0, 21.7, 20.8, 20.3, 20.2, 19.8, 19.7, 19.5, 19.3, 19.2,
(
2
1
1
H), 4.38 (d, J = 2.85 Hz, 1H), 4.36 (s, 1H), 4.24 (d, J = 9.12 Hz,
H), 4.21 (d, J = 4.63 Hz, 1H), 4.19 (d, J = 1.27 Hz, 1H), 4.18 (s,
H), 4.09−4.04 (m, 1H), 4.03 (t, J = 8.02 Hz, 1H), 3.96 (d, J = 5.27
Hz, 1H), 3.92−3.88 (m, 1H), 3.76 (dd, J = 2.89, 4.51 Hz, 1H), 3.73−
19.1, 18.7, 18.6, 18.4, 18.3, 18.0, 18.0, 17.4, 17.2, 15.2. HRMS m/z:
+
3
3
3
.71 (m, 1H), 3.70 (s, 1H), 3.69 (t, J = 2.74 Hz, 1H), 3.67 (s, 1H),
.67−3.65 (m, 1H), 3.64 (d, J = 3.72 Hz, 1H), 3.63 (s, 1H), 3.46−
.40 (m, 3H), 3.40−3.36 (m, 1H), 3.26 (d, J = 4.25 Hz, 1H), 3.23 (d,
750.4041 [M + H] . HPLC purity 97.4%, t = 17.1/17.9 min.
r
3
Δ -[L-Ala(2-benzothiazolyl)]-lugdunin (31). Yield: 19.3 mg
1
(70%). H NMR (600 MHz, DMSO-d ): δ (ppm) 8.91 (d, J = 8.64
6
J = 3.77 Hz, 1H), 3.19 (s, 1H), 3.18 (d, J = 3.47 Hz, 1H), 3.17 (s,
Hz, 1H), 8.71 (d, J = 5.04 Hz, 1H), 8.54 (d, J = 8.45 Hz, 1H), 8.28
(d, J = 9.40 Hz, 1H), 8.17 (d, J = 8.28 Hz, 1H), 8.07 (d, J = 7.90 Hz,
2H), 8.05 (s, 1H), 8.04−8.01 (m, 2H), 7.94 (d, J = 7.92 Hz, 1H),
7.89 (d, J = 8.24 Hz, 1H), 7.80 (d, J = 9.17 Hz, 1H), 7.76 (d, J = 9.39
Hz, 1H), 7.69 (d, J = 9.33 Hz, 1H), 7.49−7.43 (m, 2H), 7.39 (d, J =
7.02 Hz, 1H), 5.04 (t, J = 7.91 Hz, 1H), 5.00 (d, J = 6.54 Hz, 1H),
4.90 (d, J = 4.22 Hz, 1H), 4.89 (d, J = 4.19 Hz, 1H), 4.87 (d, J = 4.25
Hz, 1H), 4.73 (d, J = 2.13 Hz, 1H), 4.71 (d, J = 2.22 Hz, 1H), 4.64
(d, J = 2.47 Hz, 1H), 4.63−4.61 (m, 1H), 4.60 (d, J = 5.42 Hz, 1H),
4.56 (d, J = 8.13 Hz, 1H), 4.51−4.48 (m, 1H), 4.48 (s, 1H), 4.43 (s,
1H), 4.41 (s, 1H), 4.36 (d, J = 7.85 Hz, 1H), 4.24 (d, J = 4.28 Hz,
1H), 4.21 (d, J = 8.98 Hz, 1H), 4.20−4.17 (m, 1H), 4.12 (d, J = 8.93
Hz, 1H), 4.09−4.06 (m, 1H), 4.06 (s, 1H), 4.04−4.03 (m, 1H), 4.01
(d, J = 8.03 Hz, 1H), 3.97 (d, J = 8.64 Hz, 1H), 3.92 (d, J = 6.28 Hz,
1H), 3.75 (d, J = 2.23 Hz, 1H), 3.74−3.72 (m, 1H), 3.70 (d, J = 4.54
Hz, 1H), 3.67−3.65 (m, 1H), 3.58 (d, J = 3.64 Hz, 1H), 3.48 (d, J =
5.42 Hz, 1H), 3.45−3.43 (m, 1H), 3.41−3.41 (m, 1H), 3.39 (d, J =
7.17 Hz, 1H), 3.36−3.34 (m, 1H), 3.30 (s, 1H), 3.30−3.27 (m, 1H),
3.25 (s, 1H), 3.24−3.21 (m, 1H), 3.20 (d, J = 3.43 Hz, 1H), 3.19 (s,
1H), 3.17−3.15 (m, 2H), 3.09 (s, 1H), 3.08 (dd, J = 3.17, 6.56 Hz,
2H), 3.04 (d, J = 4.88 Hz, 1H), 3.02 (d, J = 3.06 Hz, 1H), 2.99 (d, J =
2.67 Hz, 1H), 2.97 (s, 1H), 2.96−2.91 (m, 1H), 2.89 (s, 1H), 2.83
(dd, J = 3.23, 4.72 Hz, 1H), 2.82−2.78 (m, 1H), 2.73 (s, 1H), 2.69 (s,
1H), 2.63−2.59 (m, 1H), 2.60−2.56 (m, 1H), 2.54 (s, 1H), 2.41 (d, J
= 9.82 Hz, 1H), 2.38 (d, J = 3.68 Hz, 1H), 2.32−2.30 (m, 1H), 2.18
(t, J = 7.30 Hz, 1H), 2.08 (d, J = 6.03 Hz, 1H), 2.05 (d, J = 3.52 Hz,
1H), 2.02 (d, J = 2.69 Hz, 1H), 2.00 (s, 1H), 1.97 (dd, J = 4.83, 7.08
Hz, 1H), 1.94 (s, 1H), 1.93−1.92 (m, 1H), 1.91 (dd, J = 2.35, 3.56
Hz, 1H), 1.90 (d, J = 1.31 Hz, 1H), 1.74 (dd, J = 6.84, 8.94 Hz, 2H),
1.56−1.50 (m, 1H), 1.39 (dd, J = 3.37, 6.40 Hz, 2H), 1.36 (s, 1H),
1.33−1.28 (m, 1H), 1.23 (s, 1H), 1.04−0.99 (m, 9H), 0.98 (d, J =
6.91 Hz, 3H), 0.92 (d, J = 7.07 Hz, 3H), 0.87 (d, J = 4.00 Hz, 3H),
0.87 (s, 6H), 0.85 (d, J = 3.19 Hz, 3H), 0.83 (d, J = 1.85 Hz, 3H),
0.82 (d, J = 1.78 Hz, 3H), 0.81 (d, J = 6.48 Hz, 3H), 0.80−0.80 (m,
3H), 0.79 (d, J = 2.21 Hz, 3H), 0.79 (d, J = 2.10 Hz, 3H), 0.78−0.76
(m, 3H), 0.75 (d, J = 3.15 Hz, 3H), 0.73 (d, J = 7.25 Hz, 3H), 0.64
(d, J = 6.79 Hz, 3H), 0.51 (d, J = 6.45 Hz, 3H), 0.43 (d, J = 6.74 Hz,
1
=
1
H), 3.10 (s, 1H), 3.08 (d, J = 3.24 Hz, 1H), 3.07 (s, 1H), 2.95 (dd, J
2.89, 6.00 Hz, 1H), 2.92 (d, J = 5.49 Hz, 1H), 2.89 (d, J = 5.64 Hz,
H), 2.84 (d, J = 9.18 Hz, 1H), 2.83−2.82 (m, 1H), 2.81 (d, J = 3.43
Hz, 1H), 2.78 (d, J = 4.37 Hz, 1H), 2.76 (s, 1H), 2.61 (d, J = 4.83 Hz,
H), 2.58 (dd, J = 8.46, 9.77 Hz, 1H), 2.55 (s, 1H), 2.53 (d, J = 3.83
Hz, 1H), 2.38 (d, J = 4.87 Hz, 2H), 2.08 (s, 1H), 2.07 (s, 1H), 2.04
s, 1H), 2.01 (s, 1H), 2.00 (d, J = 2.45 Hz, 1H), 1.98−1.97 (m, 9H),
.96 (s, 1H), 1.95 (d, J = 1.92 Hz, 1H), 1.92 (s, 1H), 1.91 (s, 1H),
.90−1.88 (m, 1H), 1.88 (d, J = 7.38 Hz, 1H), 1.83−1.73 (m, 2H),
.58−1.53 (m, 1H), 1.49−1.46 (m, 1H), 1.44−1.39 (m, 1H), 1.39−
.36 (m, 1H), 1.35 (d, J = 4.09 Hz, 1H), 1.34−1.32 (m, 1H), 1.31−
.27 (m, 1H), 1.27−1.25 (m, 1H), 1.15 (dd, J = 4.31, 7.85 Hz, 2H),
.10−1.06 (m, 3H), 1.05 (s, 12H), 1.02 (d, J = 3.98 Hz, 3H), 1.01 (s,
H), 0.93 (d, J = 6.72 Hz, 3H), 0.90 (d, J = 6.62 Hz, 3H), 0.88 (dd, J
1
(
1
1
1
1
1
1
3
=
2.51, 4.43 Hz, 9H), 0.86 (dd, J = 1.26, 6.78 Hz, 6H), 0.85−0.83 (m,
H), 0.82 (d, J = 3.39 Hz, 3H), 0.82−0.80 (m, 3H), 0.79 (d, J = 7.09
Hz, 3H), 0.77 (d, J = 7.08 Hz, 3H), 0.75 (s, 1H), 0.74−0.72 (m, 3H),
.71 (d, J = 6.82 Hz, 3H), 0.69 (d, J = 6.94 Hz, 3H), 0.65 (d, J = 6.85
3
0
1
3
Hz, 3H), 0.64 (d, J = 6.84 Hz, 3H). C NMR (150 MHz, DMSO-
d6): δ (ppm) 171.6, 171.5, 171.4, 171.3, 171.0, 170.6, 170.4, 170.2,
1
1
6
4
2
1
1
1
69.9, 169.9, 169.7, 169.2, 151.8, 151.2, 141.6, 141.5, 110.2, 110.2,
07.1, 106.8, 76.3, 76.3, 74.5, 74.5, 72.3, 72.1, 72.0, 65.3, 65.2, 64.7,
3.6, 60.8, 59.2, 57.4, 57.3, 56.8, 56.5, 54.4, 52.4, 51.7, 50.9, 50.7,
1.4, 41.1, 38.2, 37.7, 32.6, 32.0, 31.2, 30.8, 30.6, 29.6, 29.3, 29.0,
9.0, 28.5, 24.1, 24.0, 23.0, 22.3, 22.0, 21.7, 20.8, 20.3, 19.8, 19.7,
9.5, 19.1, 18.8, 18.6, 18.5, 18.4, 18.1, 18.0, 17.8, 17.4, 17.2, 17.2,
+
5.2. HRMS m/z: 734.4277 [M + H] . HPLC purity 96.1%, t = 16.7/
r
7.7 min.
3
1
Δ -[L-Ala(2-thienyl)]-lugdunin (30). Yield: 15.4 mg (60%). H
NMR (600 MHz, DMSO-d ): δ (ppm) 8.61 (d, J = 8.57 Hz, 1H),
6
8
.54 (d, J = 6.39 Hz, 1H), 8.27 (d, J = 8.58 Hz, 1H), 8.19 (d, J = 8.77
Hz, 1H), 8.17 (d, J = 8.67 Hz, 1H), 8.06 (d, J = 9.17 Hz, 1H), 8.00
d, J = 7.89 Hz, 1H), 7.80 (d, J = 5.28 Hz, 1H), 7.79 (d, J = 7.79 Hz,
(
1
9
6
6
2
1
9
3
6
1
H), 7.72 (d, J = 9.38 Hz, 1H), 7.70 (d, J = 9.41 Hz, 1H), 7.47 (d, J =
.37 Hz, 1H), 7.30 (d, J = 7.03 Hz, 1H), 7.28 (d, J = 7.98 Hz, 1H),
.93−6.91 (m, 1H), 6.90 (s, 1H), 6.89 (d, J = 7.67 Hz, 1H), 6.89−
.88 (m, 1H), 6.87 (d, J = 8.67 Hz, 1H), 6.86 (s, 1H), 4.74 (d, J =
.21 Hz, 1H), 4.72 (d, J = 2.24 Hz, 1H), 4.59 (dd, J = 4.80, 6.72 Hz,
H), 4.50 (d, J = 7.65 Hz, 2H), 4.40 (d, J = 4.10 Hz, 2H), 4.24 (t, J =
.11 Hz, 1H), 4.19 (dd, J = 8.02, 9.51 Hz, 1H), 4.10−4.03 (m, 3H),
.96 (t, J = 4.97 Hz, 1H), 3.76 (d, J = 5.89 Hz, 1H), 3.68 (dd, J =
.25, 9.63 Hz, 2H), 3.46−3.40 (m, 3H), 3.17 (dd, J = 5.66, 9.40 Hz,
H), 3.08 (dd, J = 2.64, 7.12 Hz, 1H), 3.06 (d, J = 5.40 Hz, 1H), 3.02
1
3
3H). C NMR (150 MHz, DMSO-d ): δ (ppm) 171.6, 171.5, 171.4,
6
170.9, 170.7, 170.5, 170.4, 170.2, 170.1, 170.0, 169.1, 168.8, 168.0,
166.9, 152.5, 135.0, 135.0, 134.9, 126.0, 125.9, 125.8, 125.8, 124.8,
124.8, 122.1, 122.1, 122.0, 121.9, 121.9, 72.3, 72.1, 71.9, 69.7, 69.5,
66.9, 65.2, 63.7, 60.9, 60.3, 60.1, 59.1, 57.4, 57.3, 57.3, 57.0, 56.7,
54.4, 52.6, 52.5, 51.9, 50.9, 41.4, 41.0, 38.2, 38.1, 37.7, 36.1, 35.1,
34.8, 34.6, 32.5, 32.4, 31.9, 31.3, 31.0, 30.6, 29.3, 29.0, 28.5, 28.3,
24.0, 22.9, 22.9, 22.3, 21.8, 21.6, 20.8, 19.9, 19.8, 19.7, 19.4, 19.2,
(d, J = 9.15 Hz, 1H), 2.99 (d, J = 4.41 Hz, 1H), 2.96 (d, J = 4.31 Hz,
4
047
J. Med. Chem. 2021, 64, 4034−4058