Y.-L. Jiang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1089–1091
1091
Table 1
Synthesis of brartemicin analogs and their anti-invasive activity in vitro
Entry
R
Yield (%)
Murine colon 26-L5 cells
4a–j
5a–j
Compounds
IC50 (lg/mL)
1
2
3
4
5
6
7
8
9
2-OCH3
2-CH3
4-OCH3
4-OBn (4d); 4-OH (5d)
2,3-(OCH3)2
3,4,5-(OCH3)3
3-OCH3-4-F
2,6-F2
2-CH3-6-NO2 (4i); 2-EtNH-6-CH3 (5i)
2-OH
2,3-(OH)2
4a, 82.8
4b, 87.5
4c, 81.8
4d, 68.0
4e, 74.2
4f, 68.8
4g, 64.3
4h, 83.0
4i, 76.7
5a, 70.2
5b, 63.3
5c, 69.5
5d, 64.7
5e, 60.2
5f, 58.7
5g, 82.2
5h, 66.3
5i, 35.8
5a
5b
5c
5d
5e
5f
5g
5h
1.0
NAa
NA
1.0
0.10
NA
NA
1.0
5i
1.0
10
11
12
6b
<1.0c
<1.0d
0.25
7b
2,4-(OH)2-6-CH3
Brartemicin
a
b
c
No activity.
Ref. 10.
35% inhibition at 1.0
40% inhibition at 1.0
l
l
g/mL.
g/mL.
d
7. Dollé, L.; Depypere, H. T.; Bracke, M. E. Curr. Cancer Drug Targets 2006, 6, 729.
8. Nishizawa, M.; Yamamoto, H.; Imagawa, H.; Barbier-Chassefiére, V.; Petit, E.;
Azuma, I.; Papy-Garcia, D. J. Org. Chem. 2007, 72, 1627.
9. Watanabea, R.; Yoo, Y. C.; Hata, K.; Mitobe, M.; Koike, Y.; Nishizawa, M.; Dulci,
M.; Garcia, D. M.; Nobuchi, Y.; Imagawa, H.; Yamada, H.; Azuma, I. Vaccine
1999, 17, 1484.
by methoxy-, ethylamino-, and fluoro- groups. It is noteworthy
that the 2,3-dimethoxy-substituted analog 5e was not only much
more potent than its 2,3-dihydroxyl counterpart 7, but also supe-
rior to the natural brartemicin. Compound 5e exhibited an IC50 of
0.10
lg/mL (0.15
lM), was 2.6-fold more potent than brartemicin
10. Igarashi, Y.; Mogi, T.; Yanase, S.; Miyanaga, S.; Fujita, T.; Sakurai, H.; Saiki, I.;
Ohsaki, A. J. Nat. Prod. 2009, 72, 980.
(0.39
l
M).
Unlike the natural anti-invasive inhibitor myxochelins,20 brar-
temicin analogs did not inhibit the MMP-2 and MMP-9 protease
activities that are related to degradation of extracellular matrix,
an important step for the tumor cell invasion. In addition, brartem-
icin analogs did not affect the tumor cell migration, differing from
the natural anti-invasive inhibitor lupinacidins.21 Further investi-
gation is needed to elucidate the mode of action of the brartemicin
analogs.
11. Gilbertson, S. R.; Chang, C.-W. T. J. Org. Chem. 1995, 60, 6226.
12. Neises, B.; Steglich, W. Angew. Chem., Int. Ed. 1978, 17, 522.
13. Mitsunobu, O. Synthesis 1981, 1.
14. Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V.
P. Chem. Rev. 2009, 109, 2551.
15. Typical synthetic procedures: Triphenylphosphine (300 mg, 1.14 mmol), 2,3-
dimethoxybenzoic acid (186 mg, 1.02 mmol), and diisopropyl azodicarboxylate
(226
ll, 1.14 mmol) were added to
a
stirred solution of 2,20,3,30,4,40-
hexabenzyl-a,a-D-trehalose (3, 300 mg, 0.34 mmol) in dry THF (10 mL) at
0 °C. After stirring for 2 h at the same temperature, the reaction mixture was
diluted with ice water and extracted with EtOAc. The organic layer was dried
over anhydrous MgSO4, filtered, and concentrated. The residue was purified by
silica gel column chromatography (hexane/EtOAc, 15–3:1) to give 4e
(305.6 mg, 74.2%) as a colorless oil. 1H NMR (600 MHz, CDCl3): d 7.24–7.37
(m, 16H), 7.02–7.05 (m, 2H), 5.20 (d, J = 3.6 Hz, 1H), 5.01 (d, J = 10.2 Hz, 1H),
4.88 (dd, J = 7.8, 10.8 Hz, 2H), 4.68 (q, J = 12.0 Hz, 2H), 4.58 (d, J = 10.2 Hz, 1H),
4.38 (dd, J = 3.6, 12.0 Hz, 1H), 4.28–4.32 (m, 2H), 4.08 (t, J = 9.6 Hz, 1H), 3.86 (s,
3H), 3.84 (s, 3H), 3.68 (t, J = 9.6 Hz, 1H), 3.57 (dd, J = 3.6, 9.6 Hz, 1H). MS (ESI)
m/z 1211.5 [MH+].
In summary, a series of nine novel trehalose-based brartemicin
analogs are synthesized and evaluated for their inhibitory activity
against invasion of murine colon 26-L5 carcinoma cells. Among the
synthetic analogs tested, 6,60-bis(2,3-dimethoxybenzoyl)-
a,a-D-
trehalose (5e) was found to be the most potent anti-invasive agent,
exhibited a 2.6-fold improvement with regard to the parent natural
product brartemicin and showed no cytotoxicity even at the 100
times of its effective anti-invasive concentration, and is considered
to be a promising lead molecule for the antimetastasis. Based on
our preliminary SAR analysis, more trehalose-based brartemicin
derivatives will be prepared and studied for anti-invasive activity
both in vitro and in vivo in the near future.
16. Typical procedures: To a solution of 4e (255 mg, 0.21 mmol) in a EtOAc/EtOH
(1:1) solution (5 mL) was added 10% Pd/C (100 mg), and the mixture was
stirred at room temperature under an atmosphere of H2 for 18 h. The reaction
mixture was filtered through a pad of Celite and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
(CH2Cl2/MeOH, 15:1–6:1) to give 5e (85 mg) in 60.2% yield as a white solid, mp
135–137 °C. 1H NMR (600 MHz, DMSO-d6): d 7.25 (d, J = 7.8 Hz, 1H), 7.20 (d,
J = 7.8 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 5.18 (d, J = 5.4 Hz, 1H), 4.94 (d, J = 4.8 Hz,
1H), 4.87–4.89 (m, 2H), 4.40 (d, J = 10.8 Hz, 1H), 4.30 (dd, J = 4.8, 11.4 Hz, 1H),
4.00–4.08 (m, 1H), 3.83 (s, 3H), 3.74 (s, 3H), 3.60 (td, J = 9.0, 4.8 Hz, 1H), 3.23–
3.30 (m, 2H). ESI-MS m/z 671.4 [MH+], 693.4 [MNa+].
Acknowledgment
17. Compound 5i: White solid, mp101–103 °C. 1H NMR (600 MHz, DMSO-d6): d
7.16 (t, J = 8.4 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 8.4 Hz, 1H), 6.19 (s,
1H), 5.20 (d, J = 5.4 Hz, 1H), 4.91–4.93 (m, 3H), 4.45(d, J = 10.8 Hz, 1H), 4.26 (dd,
J = 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 = 7.2 Hz, 3H). 13C
NMR (100 MHz, DMSO-d6): 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, 15.1. ESI-MS m/z 665.3 [MH+].
18. Miyanaga, S.; Obata, T.; Onaka, H.; Fujita, T.; Saito, N.; Sakurai, H.; Saiki, I.;
Furumai, T.; Igarashi, Y. J. Antibiot. 2006, 59, 698.
19. Saito, K.-I.; Oku, T.; Ata, N.; Miyashiro, H.; Hattori, M.; Saiki, I. Biol. Pharm. Bull.
1997, 20, 345.
20. Miyanaga, S.; Sakurai, H.; Saiki, I.; Onaka, H.; Igarashi, Y. Bioorg. Med. Chem.
2009, 17, 2724.
This work was supported by the National Natural Science Foun-
dation of China (NSFC, Grant No. 81072517).
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