S. R. Byeon et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4022–4025
Table 1. In vitro Ab fibril binding assay of ferulic acid (1a–b, 2a–d)
4025
2. Meyer-luemen, M. Nat. Neurosci. 2003, 6, 1.
and benzothiazole dimers (3a–g, 4a–g)
3. Nussbaum, R. L.; Ellis, C. E. N. Engl. J. Med. 2003, 348,
1356.
Compound
Kia (nM) at TZ binding sites
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Lashuel, H. A.; Petre, B. M.; Wall, J.; Simon, M.; Nowak,
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Chem. 2001, 9, 677.
FA dimer
1a
1b
0.60
0.72
1.36
1.00
0.57
0.83
1.32
0.71
0.75
1.11
0.96
>10
0.81
0.69
0.53
1.37
0.55
0.64
0.55
0.61
0.69
0.77
0.77
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
4d
4e
4f
4g
12. (a) Lee, C. W.; Zhuang, Z.-P.; Kung, M.-P.; Plo¨ssl, K.;
Skovronsky, D. M.; Gur, T. L.; Hou, C.; Trojanowski, J.
Q.; Lee, V. M. Y.; Kung, H. F. J. Med. Chem. 2001, 44,
2270; (b) Mathis, C. A.; Wang, Y.; Klunk, W. E. Curr.
Pharm. Design 2004, 10, 1469; (c) Mathis, C. A.; Wang,
Y.; Holt, D. P.; Huang, G.-F.; Debnath, M. L.; Klunk, W.
E. J. Med. Chem. 2003, 46, 2740.
PIB
FA
a Ki was calculated from nonlinear regression by Graphpad Prism soft-
ware.
13. Clark, M. A.; Duffy, K.; Tibrewala, J.; Lipard, S. J. Org.
Lett. 2003, 5, 2051.
14. Brotin, T.; Devic, T.; Lesage, A.; Emsely, L.; Collet, A.
Chem. Eur. J. 2001, 7, 1561.
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Barreau, M.; Jimont, P.; Gaererry, C. Synth. Commun.
1992, 22, 2769.
benzothiazole dimers, the presence of central secondary
(3a) or tertiary (4a) amine bridges affects the binding affin-
ities. As a whole, the linkage with a tertiary amine dis-
played higher binding affinity than that with
a
secondary amine except for 3b and 4b where the trend
was reversed. But, the kind of R1 (either halogen, CH3,
or NH2) of 3 and 4 did not show any significant influence.
17. Walczynski, K.; Guryn, R.; Zuderveld, O. P.; Timmer-
man, H. Il Farmaco 1994, 29, 684.
18. Li, Z.; Luo, F. Hauxue Yanjiu Yu Yingyong 2001, 13,
80.
19. Shevelev, S. A.; Dalinger, I. L.; Cherkasova, T. L.; Plo¨ssl,
K.; Trojanowski, J. Q.; Lee, W. M. Y. Tetrahedron Lett.
2001, 42, 8539.
20. Zhuang, Z.-P.; Kung, M.-P.; Hou, C.; Skovronsky, D. M.;
Gur, T. L.; Plo¨ssl, K.; Trojanowski, J. Q.; Lee, V. M. Y.;
Kung, H. F. J. Med. Chem. 2001, 44, 1905.
In conclusion, new FA and benzothiazole dimer deriva-
tives were synthesized. They showed excellent binding
affinities for benzothiazole binding sites of Ab1–42 fibrils
compared to PIB. In particular, 4a21 exhibited the best
binding affinity (Ki = 0.53 nM) implying that it could
be a potential probe for detection of Ab fibrils in AD
brain. However, besides specific binding affinities, since
the actual brain penetration and clearance are very
important factors in the development of AD imaging
probe, additional studies are necessary in the future.
21. Selected data. Compound 2d: 1H NMR (CDCl3,
300 MHz) d 2.89 (s, 6H), 3.84 (s, 3H), 3.87 (s, 3H), 4.32
(t, 2H, J = 5.0 Hz), 4.41 (t, 2H, J = 4.9 Hz), 6.27 (dd, 1H,
J = 8.8 Hz, 2.8 Hz), 6.35 (d, 1H, J = 15.9 Hz), 6.39 (d, 1H,
J = 2.8 Hz), 6.91 (d, 1H, J = 8.8 Hz), 7.0 (d, 1H,
J = 1.7 Hz), 7.35 (d, 1H, J = 1.7 Hz), 7.64 (d, 1H,
J = 15.9 Hz); 13C NMR(CDCl3, 75 MHz) d 41.58, 56.00,
56.15, 69.41, 71.73, 77.21, 99.85, 105.10, 110.82, 116.89,
117.37, 118.29, 125.41, 130.98, 140.37, 145.12, 147.81,
150.74, 153.67, 170.13; Anal. calcd for C21H24BrNO6: C,
54.09; H, 5.19; N, 3.00. Found: C, 53.75; H, 5.11; N, 2.89.
Compound 4a: 1H NMR (DMSO-d6, 300 MHz) d 3.15 (s,
6H), 3.86 (s, 4H), 7.01 (t, J = 7.1 Hz, 2H), 7.24 (t,
J = 7.2 Hz, 2H), 7.41 (t, J = 7.8 Hz, 2H), 7.69 (d,
J = 7.7 Hz, 2H); 13C NMR (DMSO-d6, 75 MHz) d 38.9,
50.3, 118.7, 121.2, 121.5, 126.3, 131.0, 153.3, 168.1; Anal.
calcd for C18H18N4S2: C, 60.99; H, 5.12; N, 15.80; S,
18.09. Found: C, 61.04; H, 5.22; N, 15.81; S, 17.82.
Acknowledgments
We are grateful to the Ministry of Science and Technol-
ogy (MOST) and Ministry of Commerce, Industry and
Energy (MCIE) of Korea for financial support.
References and notes
1. Kung, H. F.; Lee, C.; Zhuang, Z.; Kung, M.; Hou, C.;
Plo¨ssl, K. J. Am. Chem. Soc. 2001, 123, 12740.