kinase b (pknb) inhibitors: synthesis and sar study
TRANSCRIPT
Supporting Information
Substituted 4-oxo-crotonic acid derivatives as a new class of Protein
kinase B (PknB) inhibitors: synthesis and SAR study
Changliang Xu,a,b,† Xiaoguang Bai,a,† Jian Xu,a Jinfeng Ren,a Yun Xing,a Ziqiang Li,a Juxian Wang,a Jingjing Shi,b Liyan Yu*,a and Yucheng Wang*,a
a. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China. E-mail
address: [email protected] (L.Y.Y.); [email protected] (Y.C.W.); Tel. /Fax: +86-010-6318-7118 (L.Y.Y.); +86-010-6316-5263 (Y.C.W.).
b.Jiangsu Protein Drug Engineering Laboratory , Food & Drug Analysis and Testing Center, Jiangsu Food & Pharmaceutical Science College,
Huai’an 223003, Jiangsu, China. E-mail address: [email protected]; Tel: +86-0517-87088209.
† These authors contributed equally to this work.
NMR spectra of synthesized compounds:1b
1c
Electronic Supplementary Material (ESI) for RSC Advances.This journal is © The Royal Society of Chemistry 2016
2a
2b
2c
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.9
7
32.8
539
.10
39.2
439
.38
39.5
239
.66
39.8
039
.94
55.5
0
113.
83
129.
6113
0.10
163.
00
173.
36
197.
26
BRUKER AVANCE III 13C-NMR 2c IN DMSO-d6
NH2
O
O
O
3a
3b
3c
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
27.1
133
.79
34.4
939
.10
39.2
439
.38
39.5
239
.66
39.8
039
.94
54.9
5
113.
68
129.
21
133.
67
157.
39
174.
04
BRUKER AVANCE III 13C-NMR 3c IN DMSO-d6
O
NH2
O
4
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
8a
8b
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.2
3
128.
8412
9.05
131.
2113
4.10
136.
0113
6.89
165.
38
189.
23
BRUKER AVANCE III 13C-NMR 8b IN DMSO-d6
O
O
O
8c
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.2
5
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.2
0
128.
9912
9.63
130.
9413
3.57
136.
93
144.
83
165.
43
188.
54
BRUKER AVANCE III 13C-NMR 8c IN DMSO-d6
O
O
O
8d
8e
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.1
9
56.0
1
112.
69
120.
83
126.
8012
8.93
130.
1413
4.81
140.
77
158.
68
165.
62
190.
57
BRUKER AVANCE III 13C-NMR 8e IN DMSO-d6
O
O
OO
8f
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.2
155
.39
112.
82
120.
3712
1.53
130.
2213
1.28
136.
8513
7.41
159.
62
165.
38
188.
95
BRUKER AVANCE III 13C-NMR 8f IN DMSO-d6
O
O
O
O
8g
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.2
055
.60
56.5
0
113.
7811
4.35
120.
84
127.
0712
8.99
140.
71
153.
0415
3.15
165.
61
190.
19
BRUKER AVANCE III 13C-NMR 8g IN DMSO-d6
O
O
O
O
O
8h
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.1
655
.53
55.8
5
110.
3911
0.95
124.
3212
9.02
130.
52
136.
77
149.
02
154.
07
165.
53
186.
98
BRUKER AVANCE III 13C-NMR 8h IN DMSO-d6
O
O
O
O
O
8i
8j
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.2
5
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.1
5
72.4
5
109.
21
126.
3612
8.88
129.
3213
0.35
131.
11
137.
22
164.
8916
5.53
186.
85
BRUKER AVANCE III 13C-NMR 8j IN DMSO-d6
O
O
OO
8k
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.2
5
127.
0712
7.21
128.
6412
9.15
129.
6413
1.14
134.
8513
6.93
138.
6514
5.40
165.
43
188.
65
BRUKER AVANCE III 13C-NMR 8k IN DMSO-d6
O
O
O
8l
8m
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.1
6
124.
7212
5.12
126.
6512
8.12
128.
6512
9.74
129.
9613
1.52
133.
4513
3.50
133.
5913
9.95
165.
34
192.
55
BRUKER AVANCE III 13C-NMR 8m IN DMSO-d6
O
O
O
8n
8o
8p
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
3
52.2
7
128.
3613
0.84
131.
5013
2.12
135.
0113
6.60
165.
33
188.
50
BRUKER AVANCEⅢ13C-NMR 8p IN DMSO-d6
O
O
OBr
8q
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.2
4
113.
29
121.
68
130.
72
136.
10
149.
7315
1.97
165.
27
175.
46
BRUKER AVANCE III 13C-NMR 8q IN DMSO-d6
O
O
OO
8r
8s
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
24.8
825
.37
27.6
8
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
447
.97
52.1
9
129.
68
138.
83
165.
59
202.
32
BRUKER AVANCEⅢ13C-NMR 8S IN DMSO-d6
O
O
O
8t
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
11.7
6
19.4
4
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
52.1
5
129.
80
139.
62
165.
61
199.
42
BRUKER AVANCE III 13C-NMR 8t IN DMSO-d6
O
O
O
9a
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
9
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.6
6
60.9
3
114.
33
129.
0013
0.91
131.
36
136.
81
163.
9516
5.00
187.
14
O
O
O
O
BRUKER AVANCE III 13C-NMR 9a IN DMSO-d6
9b
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
5
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
60.9
8
128.
7812
8.99
131.
5713
4.01
136.
0213
6.64
164.
85
189.
15
BRUKER AVANCE III 13C-NMR 9b IN DMSO-d6
O
O
O
9c
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
8
21.2
3
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
60.9
7
128.
9612
9.60
131.
3013
3.58
136.
74
144.
77
164.
92
188.
51
BRUKER AVANCE III 13C-NMR 9c IN DMSO-d6
O
O
O
9d
9e
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
7
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
56.0
0
60.9
1
112.
70
120.
83
126.
8112
9.32
130.
1013
4.76
140.
68
158.
65
165.
11
190.
62
BRUKER AVANCE III 13C-NMR 9e IN DMSO-d6
O
O
OO
9f
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
8
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.3
9
61.0
0
112.
82
120.
3212
1.52
130.
2213
1.65
136.
7413
7.42
159.
61
164.
88
188.
99
BRUKER AVANCE III 13C-NMR 9f IN DMSO-d6
O
O
O
O
9g
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
6
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.5
756
.46
60.9
0
113.
7711
4.33
120.
76
127.
0812
9.35
140.
61
153.
0215
3.15
165.
10
190.
18
BRUKER AVANCE III 13C-NMR 9g IN DMSO-d6
O
O
O
O
O
9h
9i
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
14.0
1
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
60.9
5
102.
36
107.
6410
8.30
126.
2213
0.79
131.
12
136.
74
148.
29
152.
45
164.
97
186.
88
BRUKER AVANCE III 13C-NMR 9i IN DMSO-d6
O
O
O
O
O
9j
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
14.0
1
28.2
5
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
60.9
1
72.4
3
109.
19
126.
3212
8.85
129.
3213
0.70
131.
0813
7.03
164.
8716
5.03
186.
83
BRUKER AVANCE III 13C-NMR 9j IN DMSO-d6
O
O
OO
9k
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
14.0
1
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
61.0
2
127.
0612
7.19
128.
6112
9.13
129.
6113
1.51
134.
8513
6.74
138.
6514
5.38
164.
93
188.
63
BRUKER AVANCE III 13C-NMR 9k IN DMSO-d6
O
O
O
9l
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
9
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
60.9
8
117.
2712
0.23
125.
0413
0.40
131.
2713
1.59
136.
69
154.
65
162.
1216
4.93
187.
46
O
O
OO
115120125130135f1 (ppm)
117.
27
120.
23
125.
04
130.
4013
0.75
131.
2713
1.59
136.
69
BRUKER AVANCE III 13C-NMR 9l IN DMSO-d6
9m
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
4
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
61.0
3
124.
8112
5.10
126.
7112
8.15
128.
6812
9.72
129.
9213
2.00
133.
4513
3.66
139.
97
164.
88
192.
82
BRUKER AVANCE III 13C-NMR 9m IN DMSO-d6
O
O
O
9n
9o
9p
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
14.0
0
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
3
61.0
5
128.
3313
0.82
131.
8613
2.10
135.
0113
6.42
164.
83
188.
50
O
O
OBr
BRUKER AVANCE III 13C-NMR 9p IN DMSO-d6
9q
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.9
8
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
61.0
3
113.
27
121.
59
131.
08
135.
96
149.
6815
1.98
164.
77
175.
50
O
O
OO
BRUKER AVANCE III 13C-NMR 9q IN DMSO-d6
9r
9s
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
13.8
8
24.8
825
.37
27.7
139
.10
39.2
439
.38
39.5
239
.66
39.8
0
47.8
9
60.8
7
130.
00
138.
59
165.
01
202.
12
BRUKER AVANCE III 13C-NMR 9s IN DMSO-d6
O
O
O
9t
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
11.7
713
.96
19.3
7
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
60.9
9
130.
26
139.
58
165.
16
199.
54
BRUKER AVANCE III 13C-NMR 9t IN DMSO-d6
O
O
O
10a
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
9
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.6
5
68.5
3
114.
33
129.
0113
1.32
136.
66
163.
9416
4.50
187.
13
BRUKER AVANCE III 13C-NMR 10a IN DMSO-d6
O
O
O
O
10b
10c
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.2
421
.48
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
68.5
8
128.
9612
9.61
131.
7113
3.58
136.
65
144.
76
164.
43
188.
56
BRUKER AVANCE III 13C-NMR 10c IN DMSO-d6
O
O
O
10d
10e
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
6
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.9
7
68.4
6
112.
70
120.
82
126.
8112
9.73
130.
0613
4.71
140.
58
158.
62
164.
58
190.
64
BRUKER AVANCE III 13C-NMR 10e IN DMSO-d6
O
O
OO
10f
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
3
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.3
4
68.5
9
112.
82
120.
2212
1.47
130.
1613
2.05
136.
5313
7.42
159.
59
164.
34
188.
92
BRUKER AVANCE III 13C-NMR 10f IN DMSO-d6
O
O
O
O
10g
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
5
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.5
656
.44
68.4
6
113.
7511
4.34
120.
71
127.
0912
9.77
140.
52
153.
0015
3.15
164.
58
190.
20
BRUKER AVANCE III 13C-NMR 10g IN DMSO-d6
O
O
O
O
O
10h
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.5
0
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.5
455
.87
68.5
3
110.
3811
0.97
124.
3512
9.04
131.
31
136.
59
149.
03
154.
06
164.
55
187.
05
BRUKER AVANCE III 13C-NMR 10h IN DMSO-d6
O
O
O
O
O
10i
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
9
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
68.5
3
102.
35
107.
6210
8.27
126.
1713
0.79
131.
51
136.
56
148.
27
152.
42
164.
46
186.
86
BRUKER AVANCE III 13C-NMR 10i IN DMSO-d6
O
O
O
O
O
10j
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
9
28.2
5
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
68.4
8
72.4
2
109.
18
126.
3012
8.84
129.
3213
1.07
131.
1113
6.88
164.
5316
4.85
186.
84
BRUKER AVANCE III 13C-NMR 10j IN DMSO-d6
O
O
OO
10k
10l
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.5
0
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
68.6
0
117.
2912
0.24
125.
0513
0.41
131.
6013
1.67
136.
60
154.
65
162.
1216
4.45
187.
51
BRUKER AVANCE III 13C-NMR 10l IN DMSO-d6
129130131132133f1 (ppm)
130.
41
130.
76
131.
6013
1.67
O
O
OO
10m
10n
10o
10p
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
9
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
68.6
8
128.
3013
0.82
132.
1013
5.02
136.
32
164.
33
188.
54
BRUKER AVANCE III 13C-NMR 10p IN DMSO-d6
O
O
OBr
10q
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
6
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
68.6
6
113.
27
121.
50
131.
48
135.
83
149.
6315
1.98
164.
27
175.
53
BRUKER AVANCE III 13C-NMR 10q IN DMSO-d6
O
O
OO
10r
10s
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
21.4
424
.87
25.3
727
.75
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
447
.74
68.5
1
130.
46
138.
55
164.
57
202.
34
BRUKER AVANCE III 13C-NMR 10s IN DMSO-d6
O
O
O
10t
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
11.7
1
19.2
921
.47
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
3
68.6
0
130.
71
139.
51
164.
66
199.
58
BRUKER AVANCE III 13C-NMR 10t IN DMSO-d6
O
O
O
11a
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.1
938
.82
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
3
55.7
1
64.0
7
77.8
5
114.
37
129.
0113
0.93
131.
38
136.
85
155.
71
164.
0016
4.92
187.
19
BRUKER AVANCE III 13C-NMR 11a IN DMSO-d6
O
O
O
O
NH O
O
38394041f1 (ppm)
38.8
239
.10
39.2
439
.38
39.5
239
.66
39.8
039
.93
11b
11c
11d
11e
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.1
538
.80
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.9
8
63.8
9
77.7
8
112.
67
120.
81
126.
8812
9.37
130.
0013
4.69
140.
72
155.
6715
8.62
165.
05
190.
84
BRUKER AVANCE III 13C-NMR 11e IN DMSO-d6
O
O
O
NH O
O
O
11f
11g
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.1
638
.81
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
55.6
056
.46
63.8
9
77.8
1
113.
7311
4.33
120.
69
127.
1612
9.44
140.
66
152.
9915
3.15
155.
69
165.
06
190.
44
BRUKER AVANCE III 13C-NMR 11g IN DMSO-d6
O
O
O
NH O
O
O
O
11h
11i
11j
11k
11l
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.1
838
.81
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
4
64.1
0
77.8
4
117.
2912
0.24
125.
0613
0.41
131.
2713
1.59
136.
71
154.
6415
5.70
162.
1616
4.85
187.
50
BRUKER AVANCE III 13C-NMR 11l IN DMSO-d6
O
O
O
NH O
O
O
129130131132133f1 (ppm)
130.
41
130.
75
131.
27
131.
59
39.040.0f1 (ppm)
38.8
139
.10
39.2
439
.38
39.5
239
.66
39.8
039
.94
11m
-20-100102030405060708090100110120130140150160170180190200210f1 (ppm)
28.1
638
.77
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
3
64.1
7
77.8
2
124.
8412
5.05
126.
7712
8.21
128.
7312
9.71
129.
8113
2.10
133.
4513
3.74
140.
06
155.
69
164.
83
193.
07
BRUKER AVANCE III 13C-NMR 11m IN DMSO-d6
O
O
O
NH O
O
38394041f1 (ppm)
38.7
7
39.1
039
.24
39.3
839
.52
39.6
639
.80
39.9
3
125127129131133f1 (ppm)
124.
8412
5.05
126.
77
128.
21
128.
73
129.
7112
9.81
132.
10
133.
4513
3.74
11n
11o
11p
11q
11r
11s
11t
