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Scaffolded Multiple Cyclic Peptide libraries for Protein Mimics by Native Chemical Ligation
H. van de Langemheen,a M. van Hoeke,a H (Linda). C. Quarles van Ufford,a J. A. W. Kruijtzera and R. M. J. Liskampa,b
a Medicinal Chemistry & Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Sciences, Utrecht
University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
b School of Chemistry, Joseph Black Building, University of Glasgow, University Avenue, Glasgow G12 8QQ, United Kingdom.
[email protected]@glasgow.ac.uk
1
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2014
(Boc-Cys(Trt))3-TAC(N(H)Me) 4
1H NMR at 373 K
13C NMR at 373 K
2
HSQC at 373 K
COSY at 373 K
3
(H-Cys)3-TAC(N(H)Me) 5
HPLC
Minutes0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.0 37.5 40.0
Vol
ts
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
Cyclic thioester loop 1 (11a)
HPLC
Minutes0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Vol
ts
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
4
MALDI-TOF
0
10
20
30
40
50
60
70
80
90
100
%Int.
1020 1022 1024 1026 1028 1030 1032 1034 1036 1038 1040 1042 1044 1046 1048 1050 1052 1054 1056 1058 1060 1062 1064 1066 1068 1070 1072m/z
1[c].H22
473 mV[sum= 21270 mV] Profiles 1-45 Unsmoothed -Baseline 60
Data: loop1cyano0001.H22[c] 4 Jul 2012 15:38 Cal: P14R120704 4 Jul 2012 15:29 Shimadzu Biotech Axima CFR 2.9.3.20110624: Mode Reflectron, Power: 25, P.Ext. @ 1500 (bin 120)
1030.402
1031.409
1032.418
1052.3861033.425 1068.346
1054.4051039.8331031.831 1044.4721036.222
Cyclic thioester loop 2 (11b)
HPLC
Minutes0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Vol
ts
0.0
0.5
1.0
1.5
2.0
2.5
MALDI-TOF
0
10
20
30
40
50
60
70
80
90
100
%Int.
1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486m/z
1[c].H21
154 mV[sum= 8301 mV] Profiles 1-54 Unsmoothed -Baseline 60
Data: loop2cyano20001.H21[c] 4 Jul 2012 15:46 Cal: P14R120704 4 Jul 2012 15:29 Shimadzu Biotech Axima CFR 2.9.3.20110624: Mode Reflectron, Power: 30, P.Ext. @ 1500 (bin 120)
1473.607
1474.608
1475.627
1476.603
1473.028 1476.097 1477.641 1482.6991479.2361466.1441463.949 1468.474 1484.368
5
Cyclic thioester loop 3 (11c)
HPLC
Minutes0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Vol
ts
0.0
0.2
0.4
0.6
0.8
1.0
MALDI-TOF
0
10
20
30
40
50
60
70
80
90
100
%Int.
1170 1172 1174 1176 1178 1180 1182 1184 1186 1188 1190 1192 1194 1196 1198 1200 1202 1204 1206 1208 1210 1212 1214m/z
1[c].H20
156 mV[sum= 4985 mV] Profiles 17-48 Unsmoothed -Baseline 60
Data: loop3cyano0001.H20[c] 4 Jul 2012 15:32 Cal: P14R120704 4 Jul 2012 15:29 Shimadzu Biotech Axima CFR 2.9.3.20110624: Mode Reflectron, Power: 32, P.Ext. @ 1500 (bin 120)
1194.608
1195.591
1172.594
1173.784
1210.555
1196.630
1212.5441175.612 1197.838 1202.663 1209.3901178.721 1189.5061171.417 1192.4141185.9361182.142 1214.0391206.373
6
Triple-ligated product 12
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
0.0
0.5
1.0
1.5
2.0
2.5
MALDI-TOF
0
10
20
30
40
50
60
70
80
90
100
%Int.
3270 3275 3280 3285 3290 3295 3300 3305 3310m/z
1[c].N2
136 mV[sum= 3955 mV] Profiles 1-29 Unsmoothed -Baseline 60
Data: sinTACloop1io0002.N2[c] 28 Mar 2012 11:19 Cal: 120328IO 28 Mar 2012 11:27 Shimadzu Biotech Axima CFR 2.9.3.20110624: Mode Reflectron, Power: 40, P.Ext. @ 3285 (bin 178)
3287.46
3289.37
3286.493290.37
3291.37
3274.783293.38 3302.553284.583269.50 3279.82
7
Mixture 13
Mass
Triple-capped product 13 – [1-1-1] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
8
mass
[1-1-3] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.1
0.0
0.1
0.2
0.3
0.4
9
mass
[1-3-3] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.100
-0.075
-0.050
-0.025
0.000
0.025
0.050
0.075
0.100
10
mass
[1-1-2] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.10
-0.05
0.00
0.05
0.10
0.15
11
mass
[1-2-3] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
12
mass
[2-3-3] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.10
-0.05
0.00
0.05
0.10
0.15
13
mass
[1-2-2] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.1
0.0
0.1
0.2
0.3
0.4
14
mass
[2-2-3] mimic
HPLC
Minutes0 5 10 15 20 25 30 35 40 45 50
Vol
ts
-0.1
0.0
0.1
0.2
0.3
0.4
mass
15
Triple-capped TAC scaffold (for HIV-1 gp120 capture ELISA)
HPLC
Minutes0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.0 37.5 40.0
Vol
ts
-0.1
0.0
0.1
0.2
0.3
0.4
16