K.K. Sharma, R. Ravi, I.K. Maurya et al.
European Journal of Medicinal Chemistry 223 (2021) 113635
2H), 4.10 (s, 1H), 3.50e3.45 (m, 1H), 3.26e3.25 (m, 1H), 3.21e3.16
(m, 2H), 3.07e3.02 (m, 2H), 2.45 (s, 3H), 1.79e1.53 (m, 4H), 1.33 (s,
122.9, 120.8, 120.2, 117.8, 117.6, 116.3, 110.2, 106.4, 53.4, 51.1, 50.8,
50.2, 38.7, 26.4, 25.4, 24.8, 22.3; HRMS(ESI-TOF): calculated for m/z
[M þ Hþ]: 588.3047, found: 588.3029; HPLC: tR ¼ 17.8 min, 96.1%
purity.
9H); 13C NMR [100 MHz, CD3OD]:
d 171.9, 171.7, 170.9, 156.5, 153.4,
145.5,135.1,131.4,130.1,129.4,128.2,127.0,126.8,126.8,126.5,126.1,
125.1, 123.7, 121.0, 119.0, 117.7, 111.4, 108.3, 79.6, 54.8, 54.6, 53.5,
42.5, 40.3, 28.1, 27.1, 26.7, 26.3, 24.2, 20.3; HRMS(ESI-TOF): calcu-
L-His(2-tolyl)-L-Trp-L-Arg-OMe (14c). Yield: 67%. 1H NMR
[400 MHz, CD3OD]:
d 7.89 (br. s, 2H), 7.57e7.55 (m, 2H), 7.46 (br. s,
lated for m/z [M
tR ¼ 25.2 min, 95.6% purity.
N- -Boc-L-His(2-ethylphenyl)-L-Trp-L-Arg-NHBzl
Yield: 58%. 1H NMR [400 MHz, CD3OD]:
þ
Hþ]: 777.4200, found: 777.4193; HPLC:
2H), 7.30 (d, J ¼ 7.56, 1H), 7.23e7.20 (m, 1H), 7.06 (t, J ¼ 6.56, 1H),
6.98 (t, J ¼ 5.34, 1H), 4.73e4.71 (m, 2H), 4.30 (br. s, 1H), 3.63 (s, 3H),
3.14e2.83 (m, 6H), 2.45 (s, 3H), 1.67e1.50 (m, 4H); 13C NMR
a
(13d).
d
7.83 (d, J ¼ 8.00, 2H), 7.57
[100 MHz, CD3OD]: d 172.9, 172.4, 171.6, 157.5, 149.3, 143.5, 136.6,
(d, J ¼ 7.80, 1H), 7.47 (d, J ¼ 8.28, 2H), 7.34 (d, J ¼ 8.08, 1H),
7.30e7.26 (m, 2H), 7.23e7.18 (m, 5H), 7.11 (t, J ¼ 7.20, 1H), 7.03 (t,
J ¼ 7.40,1H), 4.66 (t, J ¼ 7.20,1H), 4.40 (t, J ¼ 7.10,1H), 4.33e4.30 (m,
1H), 4.25 (d, J ¼ 2.40, 2H), 3.26 (d, J ¼ 6.52, 2H), 3.19e3.14 (m, 1H),
3.09 (t, J ¼ 6.76, 2H), 3.02e2.97 (m, 1H), 2.75 (q, J ¼ 7.60, 7.56, 2H)
1.84e1.78 (m, 1H), 1.64e1.57 (m, 1H), 1.52e1.46 (m, 2H), 1.36 (s, 9H),
134.1, 130.2, 128.0, 127.4, 127.2, 127.1, 118.5, 117.1, 116.9, 111.0, 108.6,
58.7, 53.3, 52.4, 51.8, 40.8, 30.5, 29.3, 29.1, 22.2, 20.4; HRMS(ESI-
TOF): calculated for m/z [M þ Hþ]: 602.3203, found: 602.3198;
HPLC: tR ¼ 18.6 min, 95.6% purity.
L-His(2-ethylphenyl)-L-Trp-L-Arg-OMe (14d). Yield: 64%. 1H
NMR [400 MHz, CD3OD]:
d 7.95e7.88 (m, 2H), 7.61e7.51 (m, 4H),
1.28 (t, J ¼ 7.60, 3H); 13C NMR [100 MHz, CD3OD]:
d
172.9, 171.9,
7.34 (d, J ¼ 8.00,1H), 7.24 (s,1H), 7.10 (t, J ¼ 7.40,1H), 7.01 (t, J ¼ 7.30,
1H), 4.54 (t, J ¼ 6.00, 1H), 4.32 (br. s, 1H), 3.65 (s, 3H), 3.53e3.42 (m,
3H), 3.23e3.17 (m, 1H), 3.09e3.03 (m, 2H), 2.81e2.74 (m, 2H)
1.76e1.65 (m, 2H), 1.56e1.50 (m, 1H), 1.45e1.37 (m, 1H), 1.32e1.26
171.7, 157.1, 156.3, 149.5, 144.6, 138.1, 136.5, 130.1, 129.0, 128.1, 127.2,
127.0, 126.8, 126.4, 123.5, 121.3, 120.2, 118.8, 117.9, 117.6, 111.2, 108.7,
80.0, 54.7, 53.7, 53.1, 42.6, 40.4, 28.5, 28.3, 27.1, 26.1, 24.7, 14.2;
HRMS(ESI-TOF): calculated for m/z [M þ Hþ]: 791.4357, found:
791.4333; HPLC: tR ¼ 26.2 min, 95.8% purity.
(m, 3H); 13C NMR [100 MHz, CD3OD]:
d 173.3, 171.7, 167.4, 157.1,
149.7, 145.6, 136.6, 129.1, 129.0, 127.1, 126.7, 123.7, 121.1, 119.6, 118.5,
117.8, 111.0, 108.5, 54.8, 53.1, 52.3, 51.7, 40.7, 29.2, 28.5, 28.2, 26.7,
24.7, 14.4; HRMS(ESI-TOF): calculated for m/z [M þ Hþ]: 616.3360,
found: 616.3357; HPLC: tR ¼ 19.9 min, 97.0% purity.
N-
a-Boc-L-His(2-biphenyl)-L-Trp-L-Arg-NHBzl (13e). Yield:
61%. 1H NMR [400 MHz, CD3OD]:
d
8.00 (d, J ¼ 8.08, 2H), 7.90 (d,
J ¼ 8.32, 2H), 7.71 (d, J ¼ 7.32, 2H), 7.57 (d, J ¼ 7.92, 1H), 7.53 (t,
J ¼ 7.46, 2H), 7.45 (d, J ¼ 7.12, 1H), 7.33 (d, J ¼ 8.08, 1H), 7.30 (s, 1H),
7.26 (d, J ¼ 7.04, 2H), 7.21 (t, J ¼ 2.94, 2H), 7.19 (d, J ¼ 4.44, 2H), 7.10
(t, J ¼ 7.42, 1H), 7.02 (t, J ¼ 7.44, 1H), 4.66 (t, J ¼ 6.72, 1H), 4.42 (t,
J ¼ 6.72, 1H), 4.34e4.30 (m, 1H), 4.25 (s 2H), 3.27e3.15 (m, 3H),
3.11e3.03 (m, 3H), 1.85e1.79 (m, 1H), 1.66e1.44 (m, 4H), 1.36 (s,
L-His(2-biphenyl)-L-Trp-L-Arg-OMe (14e). Yield: 56%. 1H NMR
[400 MHz, CD3OD]: d 8.10 (br. s, 2H), 7.93 (br. s, 2H), 7.73 (br. s, 2H),
7.64e7.59 (m, 2H), 7.50e7.42 (m, 3H), 7.32e7.25 (m, 2H), 7.07 (t,
J ¼ 7.32, 1H), 6.98 (br. s, 1H), 4.48e4.45 (m, 1H), 4.33 (br. s, 2H), 3.62
(s, 3H), 3.21e3.16 (m, 3H), 3.04e3.01 (m, 3H),1.72e1.51 (m, 4H); 13
C
9H); 13C NMR [100 MHz, CD3OD]:
d
173.0, 171.8, 171.6, 157.1, 156.3,
NMR [100 MHz, CD3OD]: d 176.2, 172.5, 171.1, 155.0, 146.8, 140.1,
148.0, 145.0, 144.2, 139.0, 138.2, 136.6, 130.4, 128.8, 128.2, 128.1,
127.8, 127.2, 126.9, 126.9, 126.8, 126.7, 123.4, 121.5, 121.2, 118.7, 118.0,
117.8, 111.1, 108.7, 79.8, 54.7, 53.6, 53.0, 42.6, 40.4, 30.5, 29.3, 28.5,
27.1, 24.7; HRMS(ESI-TOF): calculated for m/z [M þ Hþ]: 839.4357,
found: 839.4339; HPLC: tR ¼ 27.5 min, 99.8% purity.
138.8, 137.4, 131.3, 129.1, 129.0, 128.3, 127.6, 127.5, 127.5, 127.4, 126.7,
125.8, 123.6, 121.7, 119.0, 117.7, 111.7, 107.8, 54.5, 53.3, 52.5, 52.2,
40.1, 30.2, 29.7, 27.7, 25.0; HRMS(ESI-TOF): calculated for m/z
[M þ Hþ]: 664.3360, found: 664.3345; HPLC: tR ¼ 20.9 min, 96.8%
purity.
N-
a-Boc-L-His[(2-p-(n-butylphenyl)]-L-Trp-L-Arg-NHBzl
L-His[(2-p-(n-butylphenyl)]-L-Trp-L-Arg-OMe (14f). Yield:
(13f). Yield: 64%. 1H NMR [400 MHz, CD3OD]:
d
7.93e7.82 (m, 2H),
55%. 1H NMR [400 MHz, CD3OD]:
d
7.93 (d, J ¼ 7.68, 2H), 7.59 (d,
7.56 (d, J ¼ 7.68, 1H), 7.50e7.45 (m, 3H), 7.34e7.31 (m, 1H),
7.28e7.18 (m, 6H), 7.10 (t, J ¼ 7.54, 1H), 7.02 (t, J ¼ 7.08, 1H), 4.65 (t,
J ¼ 6.74, 1H), 4.40 (t, J ¼ 6.62, 1H), 4.33e4.29 (m, 1H), 4.24 (d,
J ¼ 7.72, 2H), 3.42e3.36 (m, 1H), 3.25 (d, J ¼ 6.68, 1H), 3.18e3.08 (m,
3H), 3.03e2.97 (m, 1H), 2.75e2.70 (m, 2H), 1.82e1.78 (m, 1H),
1.66e1.61 (m, 3H), 1.42e1.41 (m, 2H), 1.37 (s, 9H), 1.29 (s, 2H),
J ¼ 7.76, 1H), 7.45 (s, 1H), 7.49 (d, J ¼ 7.64, 2H), 7.35 (d, J ¼ 8.00, 1H),
7.26 (d, J ¼ 6.80, 1H), 7.09 (t, J ¼ 7.38, 1H), 7.01 (t, J ¼ 7.32, 1H), 4.72
(t, J ¼ 7.12, 1H), 4.33e4.30 (m, 2H), 3.63 (s, 3H), 3.54e3.43 (m, 2H),
3.23e3.18 (m, 1H), 3.09e3.02 (m, 2H), 2.74 (t, J ¼ 7.38, 2H),
1.73e1.71 (m, 1H), 1.69e1.63 (m, 3H), 1.53e1.49 (m, 2H), 1.41e1.35
(m, 2H), 0.95 (t, J ¼ 7.48, 3H); 13C NMR [100 MHz, CD3OD]:
d 173.3,
0.98e0.93 (m, 3H); 13C NMR [100 MHz, CD3OD]:
d
173.3, 172.9,
171.8,167.5,157.0, 148.3,145.6,136.5,129.5,127.1,126.9,126.5,123.7,
121.1, 120.1, 119.4, 118.5, 117.8, 111.0, 108.5, 54.88, 52.4, 51.7, 51.6,
40.5, 35.1, 33.1, 28.1, 27.3, 26.5, 24.6, 21.8, 12.9; HRMS(ESI-TOF):
calculated for m/z [M þ Hþ]: 644.3673, found: 644.3660; HPLC:
tR ¼ 22.3 min, 97.1% purity.
171.8, 157.1, 156.4, 148.1, 144.6, 138.2, 136.5, 130.1, 129.5, 128.1, 127.0,
126.8, 126.3, 126.2, 123.4, 121.2, 120.2, 118.7, 117.8, 117.6, 111.1, 108.7,
79.8, 54.7, 53.0, 51.7, 42.6, 40.4, 35.0, 33.0, 29.3, 28.5, 27.1, 24.7, 21.9
12.8; HRMS(ESI-TOF): calculated for m/z [M þ Hþ]: 819.4670,
found: 819.4665; HPLC: tR ¼ 28.4 min, 99.8% purity.
L-His-L-Trp-L-Arg-NHBzl (15a). Yield: 62%. 1H NMR [400 MHz,
L-His-L-Trp-L-Arg-OMe (14a). Yield: 58%. 1H NMR [400 MHz,
CD3OD]:
d
8.81 (br. s, 1H), 7.64 (d, J ¼ 7.04, 1H), 7.49e7.43 (m, 2H),
CD3OD]:
d
8.85 (br. s, 1H), 7.64e7.44 (m, 2H), 7.35e7.26 (m, 2H),
7.33e7.23 (m, 6H), 7.08 (t, J ¼ 7.16, 1H), 7.00 (t, J ¼ 7.10, 1H),
4.41e4.24 (m, 5H), 3.78e3.63 (m, 1H), 3.43 (br. s, 1H), 3.15 (br. s,
3H), 2.81 (s, 1H), 1.84e1.58 (m, 4H); 13C NMR [100 MHz, CD3OD]:
7.10e7.02 (m, 2H), 4.49 (br. s, 2H), 4.27 (br. s, 1H), 3.68 (s, 3H),
3.48e3.45 (m, 2H), 3.25e3.19 (m, 4H), 2.02e1.66 (m, 4H); 13C NMR
[100 MHz, CD3OD]:
d
171.8, 168.7, 167.4, 157.1, 132.1, 127.8, 126.2,
d 171.6, 170.0, 167.4, 157.1, 138.3, 136.6, 134.6, 128.1, 127.1126.8, 121.3,
123.8, 121.1, 119.0, 118.5, 117.8, 111.0, 52.3, 51.7, 51.7, 40.7, 29.3, 27.4,
26.4, 24.8; HRMS(ESI-TOF): calculated for m/z [M þ Hþ]: 512.2734,
found: 512.2726; HPLC: tR ¼ 15.0 min, 95.8% purity.
118.6, 118.1, 111.0, 108.7, 54.8, 51.7, 42.6, 29.3, 28.7, 27.4, 26.4, 24.9;
HRMS(ESI-TOF): calculated for m/z [M þ Hþ]: 587.3206, found:
587.3196; HPLC: tR ¼ 20.2 min, 95.4% purity.
L-His(2-phenyl)-L-Trp-L-Arg-OMe (14b). Yield: 65%. 1H NMR
L-His(2-phenyl)-L-Trp-L-Arg-NHBzl (15b). Yield: 66%. 1H NMR
[400 MHz, CD3OD]:
d
7.85 (t, J ¼ 7.48, 2H), 7.71e7.64 (m, 3H)
[400 MHz, CD3OD]: d 7.92e7.85 (m, 2H), 7.75e7.63 (m, 4H),
7.50e7.40 (m, 3H), 7.18 (t, J ¼ 7.28, 2H), 7.08 (t, J ¼ 7.16, 1H), 4.61 (t,
J ¼ 7.80, 1H), 4.37e4.33 (m, 1H), 4.00e3.96 (m, 1H), 3.52 (s, 3H),
3.38e3.34 (m, 2H), 3.21e3.13 (m, 2H), 2.98e2.89 (m, 2H), 1.50e1.39
7.49e7.31 (m, 6H), 7.18e7.09 (m, 4H), 4.36 (br. s, 1H), 4.05 (s, 2H),
3.93e3.87 (m, 2H), 3.50e3.46 (m, 1H), 3.24e3.06 (m, 3H), 2.91 (br.
s, 2H), 1.52e1.34 (m, 2H), 1.21e1.13 (m, 2H); 13C NMR [100 MHz,
(m, 2H), 1.25e1.16 (m, 2H); 13C NMR [100 MHz, CD3OD]:
d
171.2,
CD3OD]:
d 172.8, 171.9, 167.7156.4, 145.4, 137.6, 135.9, 132.7, 129.7,
170.9, 166.0, 154.9, 143.9, 134.5, 131.2, 128.1, 125.4, 125.2, 124.6,
128.6,127.4, 127.1, 127.0, 126.6, 126.3, 124.3, 122.3, 122.1, 119.5, 119.3,
13