Synthesis and antibacterial activity of 1-N-[(S)-ω-amino-2-hydroxyalkyl] derivatives of
dibekacin, 5-deoxydibekacin, 3′-deoxykanamycin A and gentamicin B
Eijiro Umemura*, Yukou Sakamoto, Yoshiaki Takahashi and Toshiaki Miyake
Institute of Microbial Chemistry (BIKAKEN) Hiyoshi, Kawasaki, Japan.
*Corresponding author: Dr. Eijiro Umemura, Institute of Microbial Chemistry (BIKAKEN),
Hiyoshi, 3-34-17, Ida, Nakahara-ku, Kawasaki-shi, Kanagawa 211-0035, Japan.
E-mail: umemurae@bikaken.or.jp
Supplementary material
Index:
1. General information
2. Representative 1H NMR data and mass data of 2a-d
3.
13C
NMR data of arbekacin (1a) and 2a-d
4. Elemental analyses of 2a-d
5. Specific rotations of 2a-d
6. Evaluation of the minimum inhibitory concentrations (MICs)
7.
1H
NMR and 13C NMR spectra of 2a-d
S1
1. General information
1
H NMR and 13C NMR spectra were recorded on an AVANCE 500 spectrometer at 300K. The chemical
shifts (δ) were measured downfield from internal tetramethylsilane. The mass spectra were recorded on a
LTQ XL electrospray ionization (ESI) spectrometer. Elemental analyses were performed using a PERKIN
ELMER Series II CHNS/O Analyzer 2400. Optical rotations were determined with a PERKIN ELMER
Series Polarimeter Model 241.
2.
Representative 1H NMR data (500 MHz, 25% ND3/D2O) and mass data of 2a-d
Selective 1 H NMR (δ in p.p.m.)
3.
ESI-MS
(m/z) as (M + +1) Molecular formula
1'-H
J 1,'2' (Hz)
1"-H
J 1",2" (Hz)
1'"-Ha
J(Hz)
1'"-Hb
2a
5.50d
4.2
5.35d
4.2
2.88dd
8.0, 12.3
3.16m
539
C22 H46 N6 O9
2b
5.28d
3.1
5.35d
3.6
2.82dd
8.0, 12.3
3.13m
523
C22 H46 N6 O8
2c
5.12d
3.3
5.43d
3.7
2.85dd
8.0, 12.3
3.17m
556
C22 H45 N5 O11
2d
5.41d
4.1
5.70d
4.1
2.81dd
8.0, 12.3
3.17m
556
C22 H45 N5 O11
13C-NMR
spectra of arbekacin (1a) and 2a-d (125.8 MHz, 25% ND3/D2O)
Carbon
1
2
3
4
5
6
1'
2'
3'
4'
5'
6'
1''
2''
3''
4''
5''
6''
1'''
2'''
3'''
4'''
4"-CH3
N-CH3
1a
49.7
37.8
50.0
87.1
69.7
80.9
98.7
50.4
26.5
28.0
72.1
45.6
101.8
72.6
54.5
71.1
75.5
60.7
177.0
70.2
34.6
36.8
―
―
2a
52.4
37.8
49.9
87.0
69.7
87.3
100.8
50.5
26.5
28.0
72.1
45.6
101.8
72.9
54.7
71.1
75.5
60.7
57.3
75.3
32.8
37.8
―
―
2b
52.0
38.0
49.6
81.8
34.8
77.2
100.8
49.7
26.5
27.8
71.8
45.3
96.1
72.8
54.4
70.2
77.4
61.3
59.7
70.5
33.3
37.6
―
―
S2
2c
52.3
37.7
49.2
87.1
69.4
86.5
98.5
66.0
32.5
67.1
72.0
41.9
100.7
72.7
54.6
69.0
74.8
60.4
57.3
74.3
34.9
37.6
―
―
2d
50.1
37.2
49.1
87.5
69.5
85.4
99.9
72.6
73.4
72.0
72.1
42.0
100.7
73.1
63.7
74.4
68.4
―
57.3
71.3
45.1
―
22.0
32.6
4.
Elemental analyses of 2a-d
2a: Calcd for C22H46N6O9・H2O・H2CO3: C 44.67, H 8.09, N 13.59. Found: C 44.50, H 8.12, N 13.47.
2b: Calcd for C22H46N6O8・2H2O・H2CO3: C 44.58, H 8.65, N 13.36. Found: C 44.31, H 8.94, N 13.13.
2c: Calcd for C22H45N5O11・1/2H2O・1/2H2CO3: C 45.41, H 7.96, N 11.76. Found: C 45.37, H 8.26, N
11.76.
2d: Calcd for C22H45N5O11・5/2H2O・H2CO3: C 41.75, H 7.89, N 10.78. Found: C 41.50, H 8.19, N 11.01.
5. Specific rotations of 2a-d
26
2a : [α]D + 83.1° (c 0.18, H2O)
26
2b : [α]D + 99.2° (c 0.13, H2O)
26
2c : [α]D + 82.0° (c 0.16, H2O)
26
2d : [α]D + 127.3° (c 0.13, H2O)
6.
Evaluation of the minimum inhibitory concentrations (MICs)
The MICs were examined by a serial agar dilution method using Mueller-Hinton agar (Becton,
Dickinson and Company) for S. aureus, E. coli and P. aeruginosa. The test suspension was prepared at
approximately 104 CFU per 5 µl using a microplanter MIT-P inoculum replicating apparatus. The MIC
was defined as the lowest concentration of antibiotic that inhibited development of visible growth on the
agar after 18 h of incubation at 37 °C.
S3
7.
1
H NMR and 13C NMR spectra of 2a-d
Figure S1
The 1H NMR spectrum of 2a (500 MHz, 25% ND3/D2O)
Figure S2
The 1H NMR spectrum of 2b (500 MHz, 25% ND3/D2O)
S4
Figure S3
The 1H NMR spectrum of 2c (500 MHz, 25% ND3/D2O)
Figure S4
The 1H NMR spectrum of 2d (500 MHz, 25% ND3/D2O)
S5
Figure S5
The 13C NMR spectrum of 2a (125.8 MHz, 25% ND3/D2O)
Figure S6
The 13C NMR spectrum of 2b (125.8 MHz, 25% ND3/D2O)
S6
Figure S7
The 13C NMR spectrum of 2c (125.8 MHz, 25% ND3/D2O)
Figure S8
The 13C NMR spectrum of 2d (125.8 MHz, 25% ND3/D2O)
S7