Brartemicin analogs as anti-invasive agents
Y-L Jiang et al
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6,60-Bis(2-hydroxy-3-methoxybenzoyl)-a,a-D-trehalose (4g). White solid; 70%; Preparation of brartemicin analogs 4n–s
m.p. 124–1251C; [a]D25 þ 76.3 (c 5.9, MeOH). 1H NMR (600MHz, DMSO-d6)
6,60-Bis(2-methoxybenzoyl)-a,a-D-trehalose (4n). To a stirred solution of 3n
d 10.51 (s, 1H), 7.38 (dd, J ¼ 1.2, 6.6 Hz, 1H), 7.23 (dd, J ¼ 1.2, 7.2 Hz, 1H),
6.90 (t, J ¼ 7.8Hz, 1H), 5.25 (d, J ¼ 5.4 Hz, 1H), 4.97 (dd, J ¼ 4.8, 3.6 Hz, 2H),
4.89 (d, J ¼ 3.6 Hz, 1H), 4.48 (d, J ¼ 1.8Hz, 1H), 4.39 (dd, J ¼ 5.4, 6.0Hz, 1H),
4.10–4.14 (m, 1H), 3.80 (s, 3H), 3.57–3.62 (m, 1H), 3.31–3.35 (m, 1H), 3.24–
3.29 (m, 1H); 13C-NMR (150 MHz, DMSO-d6) d 175.2, 175.2, 163.1, 148.1,
144.9, 143.9, 143.9, 94.5, 72.8, 72.7, 72.5, 70.5, 25.7; ESI-MS m/z 643.6
(135 mg, 0.12mmol) in MeOH (15) and water (3ml) was added one drop of
acetic acid and the mixture was refluxed for 3 h. After removing the solvent,
the residue was purified by silica gel column chromatography (CH2Cl2/MeOH,
15B6:1) to give 4n (51 mg) in 62% yield as a white solid, m.p. 193–194 1C;
[a]D25 þ 74.6 (c 6.3, DMF). 1H NMR (600MHz, DMSO-d6)
d 7.58
(d, J ¼ 7.8Hz, 2H), 7.53 (dd, J ¼ 6.6, 9.0Hz, 1H), 5.19 (d, J ¼ 5.4 Hz, 1H),
4.95 (d, J ¼ 4.2 Hz, 1H), 4.88 (d, J ¼ 3.6 Hz, 1H), 4.81 (d, J ¼ 6.0 Hz, 1H), 4.56
(d, J ¼ 10.2Hz, 1H), 4.43 (dd, J ¼ 4.8, 6.6Hz, 1H), 3.98–4.01 (dd, J ¼ 3.6,
6.6Hz, 1H), 3.56–3.60 (m, 1H), 3.16–3.26 (m, 2H); 13C NMR (150MHz,
DMSO-d6) d 164.4, 133.4, 132.7, 131.1, 128.8, 93.9, 73.1, 71.8, 70.3, 70.1, 65.5;
[MH]þ , 665.6 [MNa]þ
.
6,60-Bis(2,4-dimethoxybenzoyl)-a,a-D-trehalose (4h). White solid; 62%; m.p.
124–1251C; [a]D25 þ 60.0 (c 4.0, MeOH). 1H NMR (600MHz, DMSO-d6) d
7.73 (d, J ¼ 8.4 Hz, 1H), 6.58–6.62 (m, 2H), 5.11 (d, J ¼ 6.0 Hz, 1H), 4.93 (d,
J ¼ 4.2 Hz, 1H), 4.90 (d, J ¼ 3.6 Hz, 1H), 4.83 (d, J ¼ 6.0 Hz, 1H), 4.33 (d,
J ¼ 10.2Hz, 1H), 4.20 (dd, J ¼ 5.4, 6.0 Hz, 1H), 4.00–4.03 (m, 1H), 3.82 (s,
3H), 3.80 (s, 3H), 3.59–3.63 (m, 1H), 3.28–3.34 (m, 1H), 3.25–3.27 (m, 1H);
13C NMR (150MHz, DMSO-d6) d 169.1, 160.6, 136.2, 130.5, 112.0, 117.8,
ESI-MS m/z 689.3 [MH]þ
Following the same procedures described for 4n, analogs 4o–s were
prepared.
.
6,60-Bis(cinnamoyl)-a,a-D-trehalose (4o). White solid; 86%; m.p. 135–136 1C;
[a]D25 þ 66.7 (c 4.5, DMF). 1H NMR (600 MHz, DMSO-d6) d 7.72 (dd, J ¼ 1.8,
4.2Hz, 2H), 7.65 (d, J ¼ 16.2Hz, 1H), 7.42 (dd, J ¼ 3.6, 8.4Hz, 3H), 7.64 (d,
J ¼ 15.6Hz, 1H), 5.16 (d, J ¼ 4.8 Hz, 1H), 4.97 (s, 1H), 4.90
(t, J ¼ 3.0 Hz, 2H), 4.32 (d, J ¼ 4.2 Hz, 1H), 4.22 (dd, J ¼ 5.4, 6.6 Hz, 1H),
4.02 (dd, J ¼ 5.4, 4.2 Hz, 1H), 3.59 (t, J ¼ 9.0 Hz, 1H), 3.31–3.34 (m, 1H),
3.19–3.24 (m, 1H); 13C NMR (150 MHz, DMSO-d6) d 166.7, 145.0, 134.5,
130.9, 129.4, 128.9, 112.0, 118.5, 94.2, 73.3, 71.9, 70.5, 70.2, 64.0; ESI-MS m/z
113.3, 94.4, 73.2, 71.9, 70.5, 70.0, 64.9; ESI-MS m/z 671.6 [MH]þ
.
6,60-Bis(2,4-dihydroxybenzoyl)-a,a-D-trehalose (4i). White solid; 71%; m.p.
125–1261C; [a]D25 þ 56.7 (c 6.7, MeOH). 1H NMR (600MHz, DMSO-d6): d
10.67 (s, 1H), 10.45 (s, 1H), 7.66 (d, J ¼ 9.0 Hz, 1H), 6.38–6.41 (m, 1H), 6.30
(d, J ¼ 1.8 Hz, 1H), 5.20 (d, J ¼ 5.4 Hz, 1H), 4.94 (dd, J ¼ 4.8, 6.0 Hz, 2H), 4.87
(d, J ¼ 3.6 Hz, 1H), 4.41 (d, J ¼ 10.2Hz, 1H), 4.34 (dd, J ¼ 5.4, 6.0 Hz, 1H),
4.08–4.12 (m, 1H), 3.57–3.61 (m, 1H), 3.25–3.35 (m, 2H); 13C NMR
(150MHz, DMSO-d6) d 169.5, 164.7, 163.2, 132.2, 1þ08.9, 104.5, 102.9, 94.4,
603.6 [MH]þ
.
6,60-Bis(3,4-dimethoxycinnamoyl)-a,a-D-trehalose (4p). White solid; 83%;
m.p. 216–2181C; [a]D25 þ 77.6 (c 5.8, DMF). 1H NMR (600MHz,
DMSO-d6) d 7.58 (d, J ¼ 15.6 Hz, 1H), 7.35 (d, J ¼ 1.8Hz, 1H), 7.22
(dd, J ¼ 1.2, 6.6Hz, 1H), 6.97 (d, J ¼ 8.4 Hz, 1H), 6.55 (d, J ¼ 15.6Hz, 1H),
5.12 (d, J ¼ 5.4 Hz, 1H), 4.94 (d, J ¼ 5.4 Hz, 1H), 4.89 (d, J ¼ 3.6 Hz, 1H), 4.87
(d, J ¼ 6.0 Hz,1H), 4.30 (d, J ¼ 12.0Hz, 1H), 4.22 (dd, J ¼ 5.4, 6.6 Hz, 1H),
3.99–4.02 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.57–3.61 (m, 1H), 3.30–3.33
(m, 1H), 3.21–3.25 (m, 1H); 13C NMR (150 MHz, DMSO-d6) d 182.5, 163.4,
161.6, 157.4, 128.9, 123.1, 115.2, 105.9, 101.0, 100.3, 95.2, 71.2, 70.8, 68.8, 66.6,
73.2, 71.9, 70.5, 70.1, 64.4; ESI-MS m/z 615.5 [MH]
.
6,60-Bis(2,4-difluorobenzoyl)-a,a-D-trehalose (4j). White solid; 66%; m.p.
205–2071C; [a]D25 þ 67.3 (c 4.9, MeOH); 1H NMR (600MHz, DMSO-d6) d
7.65 (td, J ¼ 8.4, 1.8 Hz, 1H), 7.25 (t, J ¼ 8.4Hz, 2H), 5.23 (d, J ¼ 4.2 Hz, 1H),
5.05 (s, 1H), 4.87 (d, J ¼ 3.6Hz, 2H), 4.50 (dd, J ¼ 1.8, 11.4 Hz, 1H), 4.38 (dd,
J ¼ 4.8, 11.4 Hz, 1H), 4.02 (ddd, J ¼ 1.8, 4.8, 9.6 Hz, 1H), 3.59 (t, J ¼ 9.6 Hz,
1H), 3.21–3.26 (m, 2H); 13C NMR (150MHz, DMSO-d6)
d 160.9,
150.9, 141.3, 133.5, 120.1, 115.4, 110.5, 95.6, 65.1, 39.1, 23.4, 15.1; ESI-MS
m/z 623.2 [MH]þ
56.0; ESI-MS m/z 723.7 [MH]þ
.
.
6,60-Bis(isonicotinoyl)-a,a-D-trehalose (4q). White solid; 71%; m.p.
190–191 1C; [a]D25 þ 90.0 (c 5.0, MeOH). 1H NMR (600MHz, DMSO-d6) d
8.81 (d, J ¼ 4.2Hz, 2H), 7.83 (d, J ¼ 4.2 Hz, 2H), 5.26 (s, 1H), 5.04 (s, 2H),
4.87 (d, J ¼ 3.0Hz, 1H), 4.48 (d, J ¼ 5.4 Hz, 1H), 4.38 (dd, J ¼ 5.4, 6.0 Hz, 1H),
4.14 (t, J ¼ 6.6 Hz, 1H), 3.60 (t, J ¼ 9.0 Hz, 1H), 3.30–3.34 (m, 1H), 3.26
(t, J ¼ 9.6 Hz, 2H); 13C NMR (150MHz, DMSO-d6) d 165.0. 151.3, 137.4,
6,60-Bis(2-ethylamino-6-methylbenzoyl)-a,a-D-trehalose (4k). White solid;
36%; m.p. 101–103 1C; [a]D25 þ 66.7 (c 1.5, MeOH). 1H NMR (600MHz,
DMSO-d6) d 7.16 (t, J ¼ 8.4 Hz, 1H), 6.54 (d, J ¼ 8.4 Hz, 1H), 6.45 (d, J ¼ 8.4
Hz, 1H), 6.19 (s, 1H), 5.20 (d, J ¼ 5.4 Hz, 1H), 4.91–4.93 (m, 3H), 4.45(d,
J ¼ 10.8Hz, 1H), 4.26 (dd, J ¼ 4.8, 11.4 Hz, 1H), 4.04–4.07 (m, 1H), 3.57–3.60
(m, 1H), 3.26–3.32 (m, 1H), 3.19–3.28 (m, 1H), 3.06–3.13 (m, 2H), 2.32
(s, 3H), 1.15 (t, J ¼ 7.2Hz, 3H); 13C NMR (100MHz, CD3OD) d 170.9, 150.9,
141.3, 133.5, 120.1, 115.4, 110.5, 95.6, 74.7, 73.3, 72.4, 71.5, 65.1, 39.1, 23.4,
123.0, 94.6, 73.2, 71.8, 70.5, 70.2, 65.3; ESI-MS m/z 653.5 [MH]þ
.
6,60-Bis(pyrazine-2-carbonyl)-a,a-D-trehalose (4r). White solid; 67%; m.p.
64–65 1C; [a]D25 þ 84.7 (c 5.9, H2O). 1H NMR (600MHz, DMSO-d6) d 9.20
(d, J ¼ 1.2 Hz, 1H), 8.90 (d, J ¼ 2.4Hz, 1H), 8.84 (t, J ¼ 1.8 Hz, 1H), 5.23 (d,
J ¼ 5.4 Hz, 1H), 4.94 (dd, J ¼ 4.8, 7.2 Hz, 2H), 4.89 (d, J ¼ 3.6 Hz, 1H),
4.55 (d, J ¼ 10.2Hz, 1H), 4.41 (dd, J ¼ 4.8,6.6 Hz, 1H), 4.10–4.14 (m, 1H),
3.57–3.62 (m, 1H), 3.28–3.34 (m, 1H), 3.17 (t, J ¼ 5.4 Hz, 1H); 13C NMR
(150 MHz, DMSO-d6) d 165.9, 158.8, 134.1, 131.4, 120.5, 120.4, 113.0, 93.9,
15.1; ESI-MS m/z 665.3 [MH]þ
.
6,60-Bis(4-fluoro-3-methoxybenzoyl)-a,a-D-trehalose (4l). White solid; 82%;
m.p. 210–2121C; [a]D25 þ 82.1 (c 6.7, MeOH). 1H NMR (600MHz, DMSO-
d6) d 7.63 (d, J ¼ 7.8Hz, 1H), 7.58–7.61 (m, 1H), 7.38 (dd, J ¼ 8.4, 10.8Hz,
1H), 5.24 (d, J ¼ 4.8 Hz, 1H), 5.00 (dd, J ¼ 5.4, 6.0 Hz, 2H), 4.90 (d,24 ¼ 3.6
Hz, 1H), 4.44 (d, J ¼ 10.2Hz, 1H), 4.30 (dd, J ¼ 6.6, 11.4Hz, 1H), 4.12 (t,
J ¼ 9.0 Hz, 1H) 3.89 (s, 3H), 3.60 (td, J ¼ 9.0, 5.4Hz, 1H), 3.28–3.35 (m, 1H),
3.23 (td, J ¼ 9.0, 5.4 Hz, 1H); 13C NMR (150MHz, DMSO-d6) d 164.7, 153.6,
147.1, 126.5, 122,.6, 116.2, 114.0, 93.7, 72.7, 71.4, 70.2, 69.8, 64.4, 55.9; ESI-MS
73.2, 71.9, 70.5, 70.2, 64.2, 56.1; ESI-MS m/z 555.5 [MH]þ
.
6,60-Bis(n-hexanoyl)-a,a-D-trehalose (4s). White solid; 91%; m.p. 155–156 1C;
[a]D25 þ 97.1 (c 6.8, MeOH). 1H NMR (600 MHz, DMSO-d6) d 5.08
(d, J ¼ 5.4Hz, 1H), 4.90 (d, J ¼ 4.8 Hz, 1H), 4.82 (dd, J ¼ 3.6, 7.0 Hz, 1H),
4.79 (d, J ¼ 6.0 Hz, 1H), 4.23 (d, J ¼ 5.4 Hz, 1H), 4.04 (dd, J ¼ 5.4,6.0 Hz, 1H),
3.89 (dd, J ¼ 4.8, 5.4 Hz, 1H), 3.51–3.56 (m, 1H), 3.23–3.33 (m, 1H), 3.10–3.15
(m, 1H), 2.27 (t, J ¼ 7.2 Hz, 2H), 1.49–1.54 (m, 2H), 1.23–1.29 (m, 4H),
0.84–0.87 (m, 3H); 13C NMR (150 MHz, DMSO-d6) d 173.3, 93.9, 73.2, 71.9,
m/z 647.2 [MH]þ , 669.3 [MNa]þ
.
6,60-Bis(3,4,5-trimethoxybenzoyl)-a,a-D-trehalose (4m). White solid; 59%;
m.p. 140–1421C; [a]D25 þ 58.0 (c 5.0, MeOH); 1H NMR (600MHz, DMSO-
d6) d 7.23 (s, 2H), 5.25 (d, J ¼ 6.0 Hz, 1H), 5.00 (d, J ¼ 4.8 Hz, 1H), 4.94–4.97
(m, 2H), 4.44 (d, J ¼ 9.6 Hz, 1H), 4.26 (dd, J ¼ 7.2, 11.4Hz, 1H), 4.11 (t,
J ¼ 9.6 Hz, 1H) 3.81 (s, 6H), 3.73 (s, 3H), 3.62 (td, J ¼ 9.0, 4.8 Hz, 1H), 3.29
(td, J ¼ 9.0, 6.0 Hz, 1H), 3.19 (td, J ¼ 9.0, 4.8 Hz, 1H); 13C NMR (150MHz,
70.5, 70.2, 63.5, 34.0, 31.1, 24.6, 22.3, 14.2; ESI-MS m/z 553.6 [MH]þ
.
Biological activity
DMSO-d6) d 167.0, 151.4, 149.4, 145.3, 127.3, 123.6, 115.9, 111.9, 110.7, 94.2, Cytotoxicity assay. Murine colon 26-L5 carcinoma cells were suspended (1ꢁ
73.2, 71.9, 70.4, 70.2, 63.7, 56.1, 56.0; ESI-MS m/z 731.3 [MH]þ , 753.5 105 cells per ml) in RPMI medium containing 10% FCS, L-glutamine and the
[MNa]þ
.
test compound dissolved in DMSO at various concentrations, and seeded into
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