P. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4675–4677
4677
of an extra methoxyl group decreased the up-regulatory effect on
Acknowledgment
LDLR expression.
Compound 8j is an isomer of BBR, and is called pseudoberber-
ine. It showed a higher activity on LDLR than BBR did. The factor
that might contribute to the increased activity of 8j is presumably
the change of the electropositivity at the nitrogen atom. The qua-
ternary ammonium ion at the 7-position of BBR and 8j plays an
important role in their binding affinity with the biological mole-
cules.16 However, in the BBR structure, the methoxyl at the 9-posi-
tion could form an electrostatic attraction with the quaternary
ammonium ion at the 7-position, and therefore decrease the elec-
tropositivity of BBR (Fig. 2). Accordingly, the potential of receiving
electron donation from its biological targets at the 7-position is de-
creased. Switching the methoxyl group from the 9-position (BBR)
to the 11-position (8j) separates the quaternary ammonium ion
from the methoxyl group with an increased distance. This modifi-
cation eliminates electrostatic effect between positions 7 and 9 of
BBR, and retains the electropositivity of quaternary ammonium ion
as is. Thus, as compared to BBR, 8j had an enhanced activity of
interacting with the biological targets and subsequently stabilized
LDLR mRNA.
In conclusion, we have synthesized nineteen BBR analogues
with a variety of side-chain substituents on the benzene ring
D, paralleled with which was the biological examination of their
activity on LDLR. The results suggested that the compound with
a methoxyl group at the 10- and 11-position showed the most
potent activity; and the methoxyl group at either 9- or 11-posi-
tion might provide a beneficial shoring effect for the 10-position
to obtain an optimal steric conformation. These results are of
interest to establish the SAR of BBR, and they provide the basis
for further chemical investigation. As 8j showed an increasing
activity in LDLR expression, it was selected as a potential choles-
terol-lowering drug candidate for the next-step evaluation in
animal experiments.
This work was supported by the IMB Research Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
References
1. Brown, M. S.; Goldstein, J. L. Science 1986, 232, 34.
2. Goldstein, J. L.; Brown, M. S. Nature 1990, 343, 425.
3. Grundy, S. M. Circulation 1998, 97, 1436.
4. Ansell, B. J.; Watson, K. E.; Fogelman, A. M. JAMA 1999, 282, 2051.
5. Kong, W. J.; Wei, J.; Abidi, P.; Lin, M. H.; Inaba, S.; Li, C.; Wang, Y. L.; Wang, Z. Z.;
Si, S. Y.; Pan, H. N.; Wang, S. H.; Wu, J. D.; Wang, Y.; Li, Z. R.; Liu, J. W.; Jiang, J. D.
Nat. Med. 2004, 10, 1344.
6. Abidi, P.; Zhou, Y.; Jiang, J. D.; Liu, J. W. Arterioscler Thromb. Vasc. Biol. 2005, 25,
2170.
7. Zhao, W.; Xue, R.; Zhou, Z. X.; Kong, W. J.; Jiang, J. D. Biomed. Pharmacothr.
2008, on line (PMID: 18337056).
8. Kong, W. J.; Wei, J.; Zuo, Z. Y.; Wang, Y. M.; Song, D. Q.; You, X. F.; Zhao, L. X.;
Pan, H. N.; Jiang, J. D. Metabolism 2008, 57, 1029.
9. Cho, E. Berberine hydrochloride. Pharmacopoeia of the People’s Republic of China
1990, 2, 437.
10. Luo, L. J. Chin. J. Med. 1955, 41, 452.
11. Lau, C. W.; Yao, X. Q.; Chen, Z. Y.; Ko, W. H.; Huang, Y. Cardiovasc. Drug Rev.
2001, 19, 234.
12. Altern. Med. Rev.. 2000, 5, 175.
13. Chen, S. Q.; Lin, W. F.; Zang, J. H.; Liu, J. Z.; Qi, S. H.; Zhang, L. Q.; Song, G. L. CN
Patent 1164588C, 2004.
14. Pan, J. F.; Yu, C.; Zhu, D. Y.; Zhang, H.; Ren, J.Y. CN Patent 1190425C. 2005.
15. Analytical data for selected final compound 8j. Mp 242–244 °C; 1H NMR
(400 MHz, DMSO-d6,) d3.19 (t, 2H, J = 6.4 Hz, 5-CH2), 3.99 (s, 3H, 11-OCH3),
4.07 (s, 3H, 10-OCH3), 4.76 (t, 2H, J = 6.4 Hz, 6-CH2), 6.17 (s, 2H, –OCH2O–), 7.09
(s, 1H, 4-CH), 7.57 (s, 1H, 1-CH), 7.71 (s, 1H, 12-CH), 7.73 (s, 1H, 9-CH), 8.76 (s,
1H, 13-CH), 9.52 (s, 1H, 8-CH); MS (m/z): 336 M+; Anal. calcd for C20H18NO4Cl
Á1.5 H2O (in %): C, 60.23; H, 5.30; N, 3.51. Found: C, 60.26; H, 5.23; N, 3.15.
16. Xiao, L. B.; Lang, C. H.; Guang, D. Y. Bioorg. Med. Chem. 2006, 16, 1380.