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S1
Supporting Information
Synthesis, SAR and biological studies of sugar amino acid based almiramide analogues: N-methylation leads the way
Dipendu Das,a Hina P. A. Khan,b Rahul Shivahare,c Suman Gupta,c Jayanta Sarkar,d Mohd. Imran
Siddiqui,e Ravi Sankar Ampapathi,*f Tushar Kanti Chakraborty*b
CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow
226031, India; Department of Organic Chemistry, Indian Institute of Science, CV Raman Road,
Bengaluru 560012, India
tushar@orgchem.iisc.ernet.in
Table of Contents:
1. General Experimental Details and Instrumentation: S2
2. Spectra (1H and 13C NMR) of Compounds: S3-S34
3. SAR studies S35-S40
4. NMR studies S41-S52
5. RPHPLC Chromatograms S53-S64
Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2017
S2
General Experimental Details:
All the reactions were carried out under an inert atmosphere in oven-dried glassware using dry
solvents, unless otherwise stated. All chemicals purchased from commercial suppliers were
used as received unless otherwise stated. Reactions and chromatography fractions were
monitored by Merck silica gel 60 F-254 glass TLC plates and visualized using UV light, 7%
ethanolic phosphomolybdic acid-heat, 2.5% ethanolic anisaldehyde (with 1% AcOH and 3.3%
conc. H2SO4), ninhydrin or chlorine/o-tolidine-heat as developing agents. Flash column
chromatography was performed with 100-200 mesh silica gel and yields refer to
chromatographically and spectroscopically pure compounds.
Instrumentation:
All NMR spectra were recorded in CDCl3 or in DMSO-d6 on a 300, 400 and 500 MHz instruments
at 300 K and are calibrated to residual solvent peaks (CHCl3 7.26 ppm and 77.0 ppm, DMSO 2.50
ppm and 40 ppm). Multiplicities are abbreviated as: s = singlet; d = doublet; t = triplet; q =
quartet; m = multiplate. All IR data were recorded as neat liquid or KBr pellets using a Perkin
Elmer’s RX I FTIR spectrophotometer. Mass spectra were obtained under electron spray
ionisation (ESI) and HRMS spectra were taken with a 3000 mass spectrometer using Waters
Agilent 6520-Q-TofMS/MS system and JEOL-AccuTOF JMS-T100 LC. RP-HPLC was performed on
a waters HPLC system and Shimadzu's ISO 9001 HPLC system (model no. LC-20AD) equipped
with a 5 µ SunFire C18 column (4.6 × 250 mm) and 5 µ Shimadzu's C18 column (4.6 × 250 mm)
respectively in combination with eluants A (H2O) and B (MeCN) with flow rate: 0.8 mL/min and
photodiode array detector setting of λ = 210-254 nm.
S3
Spectra (1H and 13C NMR) of Compounds:
1H NMR spectrum (CDCl3, 400 MHz) of compound 8.
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
5.972
1.017
3.000
12.065
1.225
1.991
1.002
2.000
0.791
13C NMR spectrum (CDCl3, 100 MHz) of compound 8.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S4
1H NMR spectrum (CDCl3, 400 MHz) of compound 11.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
9.007
2.196
1.268
3.050
1.009
3.012
1.009
3.004
1.002
1.030
1.000
1.099
0.924
1.038
2.067
4.498
13C NMR spectrum (CDCl3, 100 MHz) of compound 11.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S5
1H NMR spectrum (CDCl3, 400 MHz) of compound 14.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
14.054
9.195
2.597
1.014
2.372
3.008
5.356
1.011
3.143
1.044
2.053
1.093
1.060
1.124
1.000
1.002
1.062
3.240
4.006
13C NMR spectrum (CDCl3, 100 MHz) of compound 14.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S6
1H NMR spectrum (CDCl3, 400 MHz) of compound 19.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
7.613
1.455
15.807
1.303
3.001
2.263
3.000
6.617
0.917
3.009
2.039
1.117
1.015
1.072
0.922
1.007
2.174
4.571
13C NMR spectrum (CDCl3, 100 MHz) of compound 19.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S7
1H NMR spectrum (CDCl3, 400 MHz) of compound 20.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
22.115
2.068
14.593
1.435
5.871
2.010
3.000
5.090
1.146
3.034
1.111
1.067
2.072
1.017
1.007
1.028
1.009
2.011
0.981
2.080
5.192
13C NMR spectrum (CDCl3, 100 MHz) of compound 20.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S8
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 20.
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 20.
S9
1H NMR spectrum (CDCl3, 300 MHz) of compound 4A.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
19.020
2.588
4.724
9.133
2.205
2.146
3.111
4.878
0.986
3.004
1.089
2.080
2.183
1.019
1.000
2.771
9.250
13C NMR spectrum (CDCl3, 75 MHz) of compound 4A.
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S10
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4A.
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4A.
S11
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4B.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
19.922
3.152
9.724
2.063
1.407
5.038
8.034
2.017
1.768
2.242
0.950
1.000
6.277
0.892
2.255
2.754
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4B.
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S12
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4C.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
27.107
4.005
3.276
6.159
24.189
5.130
11.767
1.968
0.986
0.964
1.389
2.359
1.010
5.000
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4C.
210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S13
1H NMR spectrum (CDCl3, 400 MHz) of compound 21.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
7.509
1.342
14.879
2.624
2.380
1.155
1.206
1.136
3.176
1.031
1.095
1.000
2.114
4.045
13C NMR spectrum (CDCl3, 100 MHz) of compound 21.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S14
1H NMR spectrum (CDCl3, 400 MHz) of compound 22.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
20.142
1.278
13.374
1.123
4.469
1.064
1.062
5.244
1.005
1.049
1.000
2.004
6.959
13C NMR spectrum (CDCl3, 100 MHz) of compound 22.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S15
1H NMR spectrum (DMSO-d6, 300 MHz) of compound 4D.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
20.059
1.582
5.862
3.736
4.297
5.169
1.044
1.080
1.078
3.381
2.091
1.075
5.513
1.022
1.003
1.040
1.000
13C NMR spectrum (DMSO-d6, 75 MHz) of compound 4D.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S16
1H NMR spectrum (DMSO-d6, 300 MHz) of compound 4E.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
20.650
1.793
10.200
4.546
4.762
2.057
1.007
1.084
2.158
1.000
1.005
5.002
1.116
1.167
0.996
2.003
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4E.
-10210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S17
1H NMR spectrum (CDCl3, 400 MHz) of compound 4F.
8 7 6 5 4 3 2 1 ppm
22.795
7.857
4.107
3.788
3.361
2.056
3.000
5.448
1.002
3.073
2.205
1.169
2.285
1.133
1.145
1.189
3.350
5.359
13C NMR spectrum (CDCl3, 100 MHz) of compound 4F.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S18
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4G.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
27.251
9.362
4.084
7.828
2.384
5.149
3.000
1.056
1.005
1.490
3.749
1.006
1.718
10.120
1.015
1.003
1.501
1.504
0.824
1.436
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4G.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S19
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4H.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
20.071
7.591
2.816
5.301
12.368
2.484
3.013
2.631
3.058
13.679
2.258
1.005
1.022
2.000
0.730
5.601
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4H.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S20
1H NMR spectrum (CDCl3, 400 MHz) of compound 4I.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
12.043
2.225
4.657
2.016
2.049
2.080
3.007
5.041
1.003
3.005
2.000
1.002
1.991
1.008
0.998
1.000
3.039
5.015
13C NMR spectrum (CDCl3, 100 MHz) of compound 4I.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S21
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4J.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
12.272
2.141
2.167
4.403
1.010
2.048
4.483
4.456
1.005
1.071
1.017
2.089
1.024
1.087
6.439
1.005
1.001
1.010
1.000
1.001
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4J.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S22
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4K.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
14.628
3.727
1.603
4.030
1.378
14.828
14.249
3.982
1.378
1.474
2.097
1.507
5.000
1H NMR spectrum (CDCl3, 400 MHz) of compound 4L.
8 7 6 5 4 3 2 1 ppm
15.845
9.101
2.272
3.097
1.236
2.135
2.230
3.026
5.595
1.002
3.121
2.001
1.002
2.052
1.053
1.009
1.000
4.214
4.175
S23
13C NMR spectrum (CDCl3, 100 MHz) of compound 4L.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4M.
8 7 6 5 4 3 2 1 ppm
15.593
9.038
2.137
2.105
2.151
2.007
4.408
4.398
1.002
1.012
1.001
2.056
1.005
1.035
6.435
1.001
1.016
1.009
1.000
1.007
S24
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4M.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4N.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
17.604
11.514
2.596
5.036
11.473
5.822
2.217
10.904
2.195
1.233
1.065
2.000
0.716
5.288
S25
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4N.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (CDCl3, 400 MHz) of compound 4O.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
16.565
17.442
2.594
5.342
2.134
3.089
5.070
1.002
3.025
2.002
1.006
2.001
1.000
1.001
1.003
3.000
5.300
S26
13C NMR spectrum (CDCl3, 100 MHz) of compound 4O.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4P.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
17.732
12.826
2.397
2.359
2.416
2.233
5.035
4.908
1.013
1.034
1.091
2.268
1.002
1.086
6.519
1.001
1.009
1.064
1.000
1.010
S27
13C NMR spectrum (DMSO-d6, 75 MHz) of compound 4P.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4Q.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
18.272
16.657
2.572
6.296
9.539
4.494
12.858
2.753
1.323
0.863
2.187
0.430
5.000
S28
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4Q.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (CDCl3, 400 MHz) of compound 4R.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
13.839
10.914
2.518
9.433
2.458
3.000
6.173
1.096
3.295
2.107
1.091
1.137
1.038
3.676
1.187
1.027
1.071
1.161
3.187
4.347
S29
13C NMR spectrum (CDCl3, 100 MHz) of compound 4R.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 300 MHz) of compound 4S.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
15.526
20.130
3.928
5.236
3.171
2.006
6.248
0.972
0.788
1.161
3.007
1.143
1.199
2.278
1.064
7.172
0.689
0.647
1.063
1.079
1.008
S30
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4S.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4T.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
13.113
9.938
2.265
2.426
5.145
15.206
11.183
2.060
1.975
0.900
4.026
0.581
1.067
5.000
S31
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4T.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (CDCl3, 400 MHz) of compound 4U.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
14.606
2.760
5.323
6.859
2.368
2.032
3.166
5.909
1.053
3.145
2.155
1.101
2.173
1.153
1.001
1.000
8.004
6.847
S32
13C NMR spectrum (CDCl3, 100 MHz) of compound 4U.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4V.
8 7 6 5 4 3 2 1 ppm
15.151
3.004
5.298
2.556
2.639
2.406
2.546
5.262
5.148
1.020
1.064
1.152
2.401
1.056
1.156
14.775
1.024
1.039
1.040
1.094
1.000
S33
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4V.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
1H NMR spectrum (DMSO-d6, 400 MHz) of compound 4W.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
14.662
2.649
4.688
2.684
2.600
2.579
9.357
5.026
25.555
1.903
1.047
0.903
2.000
0.622
10.703
S34
13C NMR spectrum (DMSO-d6, 100 MHz) of compound 4W.
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
S35
SAR studies:
Method:
Molecules were drawn and minimized in MOE followed by partial charge calculation
using AMBER99. Structures were subsequently subjected to molecular dynamics simulation at
300 K and AMBER99 force field in vacuum with 100 ps of equilibrium run followed by
production run for 500 ps. Resulting structures were analyzed in Chimera.
Table S1. Listing the phi and psi values for compounds with their corresponding
activities:
Compound Antiamastigote activity (IC50,µM)
(MQ/amast. model)
phi1 psi1
4A >100 -61.755 -0.71
4B >100 -134.198 -1.212
4C 26.41 49.707 59.072
4D >100 -59.787 -16.771
4E >25 -59.901 10.461
4F 92.18 -65.788 -30.967
4G >100 -75.104 -4.855
4H 56.48 113.958 -46.977
4I >100 -59.891 -14.16
4J >100 -46.942 -25.482
4K >100 -137.28 59.323
S36
4L 60.67 -67.65 -8.03
4M >100 -62.493 -23.785
4N 26.67 58.367 46.577
4O 68.48 -63.718 -5.054
4P >100 -74.749 10.65
4Q 10.10 66.404 59.106
4R >50 -44.178 -23.69
4S >100 -68.138 -13.506
4T 10.92 50.737 53.02
4U 22.86 -50.932 -25.19
4V >100 -53.618 -10.524
4W 13.63 66.5 61.3
S37
Effect of H-bonding on the structural changes in the domain of peptides:
The amide proton containing molecules form the hydrogen bond between the carbonyl
oxygen of the first residue and amide proton of the third residue and adopts a particular tight
gamma turn resulting the N-terminal hydrophobic chains to turn around the backbone leading
to the disruption of coiled secondary structure and also in the reduction of hydrophobic surface
area.
4A 4B 4C
4D 4E
S38
4F 4G 4H
4I 4J 4K
S39
4L 4M 4N
4O 4P4Q
S40
4R4S
4T
4U 4V 4W
S41
NMR Studies: Solution NMR spectra were recorded on 500 MHz spectrometers at room
temperature or else as mentioned using 2-10 mM concentration of peptides in appropriate
solvents using TMS as internal standard or the solvent signals as secondary standards and the
chemical shifts (δ) are shown in ppm scales. 13C spectra were recorded at 125 MHz with
complete proton decoupling. The proton resonance assignments were carried out by using 1H-1H Two-dimensional total correlation spectroscopy (TOCSY), and Rotating frame nuclear
Overhauser effect spectroscopy (ROESY). All the experiments were carried out in the phase
sensitive mode. The spectra were acquired with 1024x256 or 2048x192 free induction decays
(FID) containing 8-16 transients with relaxation delay 1-2 s. The TOCSY experiments were
performed with mixing time of 0.08s, and spin-locking field of 10 kHz. The two dimensional data
were processed with Gaussian apodization in both the dimensions. The ROESY experiments
were performed with mixing times of 0.2 to 0.3 s, and a spin locking field of about 2.5 kHz.
Variable temperature (VT) studies were carried out by varying temperature by 10C for every
increment from 20C-70C. Small changes in amide proton chemical shifts (ppb/K) during VT
studies have been used to indicate their participation in H-bonding.
Table S2: Chemical shift (δ in ppm) and coupling constants (J in Hz) for 4P in DMSO-d6 (~8 mM,
500 MHz, 300 K)
Res NH CαH CβH CγH CδH CεH δ/T
1PHE 7.57 (d, 3JNH-
cαH=8.5 Hz)
4.425 (ddd, 1H, 3JCαH-cβH = 5.3 Hz, 3JCαH-
cβ'H=7.9 Hz)
2.96 (dd, 1H, 3JCβH-cγH = 5.3 Hz, 3JCβH-cβ’H =13.2 Hz)
2.91 (dd, 1H, 3JCβ'H-cγH= 7.9 Hz)
- - - 3.25
2MAA 8.13 (d, 1H, 3JNH-
CαH=6.0)
4.29 (d, 1H, 3JCαH-cβH = 1.8 Hz)
3.813 (t, 1H, 3JcβH-CγH = 1.8Hz)
3.63 (dd, 1H, 3JcγH-CδH
= 2.7 Hz)
3.89 (dt, 1H, 3JCδH-
CH, H’ = 6.8 Hz)
3.26 (m, 1H), 3.14 (m, 1H)
10.75
S42
3VAL 7.65 (d, 1H, 3JNH-
Hα=8.8 Hz)
4.15 (dd, 1H, 3JCαH-cβH=6.8 Hz)
1.93 (dd,3JCbH-
cγH=6.8 Hz)0.822 (d, 6H)
5.75
4VAL 7.83 (t, 3JNH-Hα
=8.9
4.17 (dd,3JCαH-
cβH=6.8 1.95 (dd,3JCαH-
cβH= 6.80.804 (d, 6H)
4.50
Acetyl --- 2.136 (m,2H) 1.515(m,2H) 1.254 (m,2H)
1.537 (m,2H)
2.53 (m, 2H)
4.0 for 7.45
Figure S1: 2D-TOCSY NMR spectrum (DMSO-d6, 400 MHz) of compound 4P
S43
Figure S2: 2D-ROESY NMR spectrum (DMSO-d6, 400 MHz) of compound 4P
Figure S3: Stacked 1H-spectra of 4P collected from 293 K-333 K
S44
Figure S4: 2D-TOCSY NMR spectrum (DMSO-d6, 400 MHz) of compound 4V
Figure S5: 2D-ROESY NMR spectrum (DMSO-d6, 400 MHz) of compound 4V
S45
Figure S6: Stacked 1H-spectra of 4V collected from 293 K-333 K
Table S3: Chemical shift (δ in ppm) and coupling constants (J in Hz) for 4V in DMSO-d6 (~8 mM,
500 MHz, 300K)
Residues NH CαH CβH CγH CδH CεH δ/T
1PHE 7.56 (d, 3JNH-cαH = 8.4
4.41 (ddd, 1H, 3JCαH-cβH = 5.4 Hz, 3JCαH-
cβ'H=7.8 Hz)
2.93 (m, 2H)
----- ---- 3.6
2MAA 8.11 (t, 3JNH-cεH,
CεH’=5.7 Hz)
4.26 (d, 3JCαH-
cβH = 1.9 Hz)3.81 (1H, 3JcβH-CγH = 1.9Hz)
3.62 (dd, 1H, 3JcγH-
CδH = 2.7 Hz)
3.87 (dt, 1H, 3JCδH-
CH, H’ = 6.8 Hz)
3.14(m, 1H), 3.25 (m, 1H)
6.3
3VAL 7.62 (d, 3JNH-cαH = 8.9
4.14 (d, 3JCαH-
cβH = 7.31.92 (m, 1H)
0.82 (d, 6H)
6.0
4VAL 7.81 (d, 3JNH-cαH = 8.9 Hz)
4.16 (dd, 3JCαH-cβH=7.3 Hz)
1.94 (m, 1H)
0.80 (d, 6H)
___ ___ 4.8
S46
Acetyl ---- 2.134 1.462 1.212 __ __ 4.5 for 7.44
Figure S7: Expanded ROESY spectra of 4P and 4V in DMSO-d6 (~8 mM, 300 K). The nOes
MaaCH(pro-S)↔PheNH, MaaCH(pro-R)↔PheNH, MaaCH↔PheNH, MaaCH(pro-
R)↔PheNH, MaaCH↔PheNH, MaaCH↔PheNH, MaaNH↔PheNH are marked as 1-
7.
7.527.58
3.2
4.0
3.8
3.6
3.4
1
2
3
(A)
S47
Figure S8: 2D-TOCSY NMR spectrum (DMSO-d6, 400 MHz) of compound 4Q
Figure S9: 2D-ROESY NMR spectrum (DMSO-d6, 400 MHz) of compound 4Q
S48
Table S4: Chemical shift (δ in ppm) and coupling constants (J in Hz) for 4Q in DMSO-d6 (~8 mM, 500 MHz, 300K)
Figure S10: 2D-TOCSY NMR spectrum (DMSO-d6, 400 MHz) of compound 4W
AA NH CH CH CH CH CH Others /T1PHE ----- 5.43 2.70,
3.13----- ----- ----- 2.78 -----
2MAA ----- 4.65 ----- ----- 4.02 ----- ----- -----3VAL ----- 4.98 2.19 0.65, 0.81 ----- ----- 2.97 -----4VAL ----- 5.04 2.19 0.71, 0.77 ----- ----- 2.81 -----ACetyl ----- 2.134 1.462 1.212 ----- ----- ----- -----
S49
Figure S11: 2D-ROESY NMR spectrum (DMSO-d6, 400 MHz) of compound 4W
Molecular dynamics: The Discovery studio 3.0 client Program was used for the restrained
molecular dynamics and energy minimization calculation using CHARMm force field with
default parameters throughout the simulation with the aid of distance dependent dielectric
constant = 38. A force constant of 10 K cal/Å and 5 K cal/Å was used for distance and torsional
restraints respectively. Minimizations were done initially with steepest descent algorithm
followed by conjugate gradient methods for maximum 1000 iterations or RMS Deviation of
0.001 Kcal /mol, whichever was earlier. The molecules were initially equilibrated for 5ps and
then after subjected to 1nS production run. Starting from 50 K, they were heated to 300 K in
five steps increasing the temperature 50 K at each step. 20 structures were stored from the
production run and are again energy minimized with the above mentioned protocol. Out of
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these 20 structures 15 least energy structures were superimposed and are presented as Stereo
view figures for each foldamer.
Figure S12. Stereo view of 15 minimum energy superimposed structures with H-bond for 4P.
Table S5. Distance constraints used in MD calculation for 4P derived from ROESY experiment in DMSO-d6 (~8 mM, 500 MHz, 300 K).
Residue-Residue Volume Distance (Max.) Distance (Min.)1PheCH-HN 6.07E+06 4.5 3.5
1PHECH-3ValHN 5.45E+06 4.5 3.52MAACH-1PHEHN 3.40E+06 4.5 3.5
2MAACH-HN 4.42E+05 5.5 4.52MAACH-1PHEHN 6.70E+06 4.5 3.5
2MAA CH-HN 3.87E+06 4.5 3.52MAACH(pro-R)-HN 5.82E+06 4.5 3.52MAACH(pro-S)-
1PHEHN 4.04E+05 5.5 4.52MAAHE(pro-S)-HN 6.83E+06 4.5 3.5
2MAAHG-HN 4.79E+06 4.5 3.53VALCH-2MAAHN 2.39E+07 5.5 4.53VALCH-2MAAHN 3.86E+06 4.5 3.53VALHG-2MAAHN 2.28E+06 4.5 5.54VALHG-1PHEHN 9.50E+05 5.5 4.5
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Figure S13. Stereo view of 15 minimum energy superimposed structures with H-bond for 4V.
Table S6. Distance constraints used in MD calculation for 4V derived from ROESY experiment in DMSO-d6 (~8 mM, 500 MHz, 300 K).
Residue-Residue Volume Distance (Max) Distance (Min)2CH-TNH2-A 3.60E+05 5.5 4.5
1PHE CH-2MAACH 6.09E+05 5.5 4.53VALCH-2MAACH 6.42E+05 5.5 4.5
2MAAHE(pro-R)-TNH2-A 6.71E+05 5.5 4.52MAACH-HN 8.27E+05 5.5 4.5
2MAAHN-1PHEHN 8.65E+05 5.5 4.52MAACH(pro-R)-1PHEHN 1.04E+06 4.5 3.5
1PHEHN-TNH2-A 1.40E+06 4.5 3.53VALC,'H-1PHEHN 1.64E+06 4.5 3.5Ace-CH-4VALHN 2.39E+06 4.5 3.52MAACH-1PHEHN 2.44E+06 4.5 3.5
3VALCH,CH'-2MAACH 2.65E+06 4.5 3.52MAAHG-CH 3.35E+06 4.5 3.5
TNH2-CH-1PHEHN 3.60E+06 4.5 3.5ACHE-ACFH-Ar 3.79E+06 4.5 3.5
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3VALCH,C'H-2MAAHD 3.79E+06 4.5 3.51PHEC,’H-TNH2-A 4.47E+06 4.5 3.52MAACH(pro-R)-CH 4.73E+06 4.5 3.5Ace-CH-4VALHN 5.72E+06 4.5 3.52MAACH-1PHEHN 6.82E+06 4.5 3.52MAACH-HN 7.26E+06 4.5 3.52MAACH-HD 8.27E+06 4.5 3.52MAACH-HN 9.87E+06 4.5 3.5
1PHEC,’H-HN 1.02E+07 3.5 2.53VALHN-4VALHN 1.13E+07 3.5 2.54VALHN-3VALHN 1.17E+07 3.5 2.53VALCH-2MAAHN 1.18E+07 3.5 2.52MAACH-1PHEHN 1.23E+07 3.5 2.5
3VALC.'H-2MAAHN 1.24E+07 3.5 2.52MAAHN-3VALHN 1.26E+07 3.5 2.51PHECH-HN 1.28E+07 3.5 2.52MAACH-HD 1.32E+07 3.5 2.54VALCH-HN 1.38E+07 3.5 2.5
1PHECH-TNH2-A 1.39E+07 3.5 2.53VALCH,C'H-ACHE 1.44E+07 3.5 2.5
2MAACH(pro-S)- CH 1.46E+07 3.5 2.52MAACH(pro-R)-CH 1.58E+07 3.5 2.5
2MAACH-CH 1.61E+07 3.5 2.54VALCH-HN 1.62E+07 3.5 2.5
2MAACH(pro-S)-HN 2.08E+07 3.5 2.52MAACH-CH 2.09E+07 3.5 2.5
4VALCH,C'H-HN 2.12E+07 3.5 2.53VALCH-HN 2.18E+07 3.5 2.5
3VALCH,C'H-HN 2.27E+07 3.5 2.52MAA CH(pro-S)- CH 2.27E+07 3.5 2.52MAA CH(pro-R)-CH 2.70E+07 3.5 2.5AceCH -ACFH-Ar 4.21E+07 3.5 2.5
2MAACH(pro-R)-HN 4.67E+07 3.5 2.5Ace-CH-4VALHN 5.09E+07 3.5 2.53VALHN-2MAAHN 6.81E+07 3.5 2.54VALCH-3VALHN 7.18E+07 3.5 2.53VALCH-2MAAHN 7.49E+07 3.5 2.52MAACH -CH 1.21E+08 3.5 2.5
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RPHPLC Chromatograms:
HPLC chromatogram of compound 20.
HPLC chromatogram of compound 4A.
S54
HPLC chromatogram of compound 4B.
HPLC chromatogram of compound 4C.
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HPLC chromatogram of compound 4D.
HPLC chromatogram of compound 4E.
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HPLC chromatogram of compound 4F.
HPLC chromatogram of compound 4G.
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HPLC chromatogram of compound 4H.
HPLC chromatogram of compound 4I.
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HPLC chromatogram of compound 4J.
HPLC chromatogram of compound 4K.
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HPLC chromatogram of compound 4L.
HPLC chromatogram of compound 4M.
S60
HPLC chromatogram of compound 4N.
HPLC chromatogram of compound 4O.
S61
HPLC chromatogram of compound 4P.
HPLC chromatogram of compound 4Q.
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HPLC chromatogram of compound 4R.
HPLC chromatogram of compound 4S.
S63
HPLC chromatogram of compound 4T.
HPLC chromatogram of compound 4U.
S64
HPLC chromatogram of compound 4V.
HPLC chromatogram of compound 4W.
Recommended