Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: synthesis, structure-activity relationships, and cholesterol-lowering efficacy

  • J Med Chem. 2009 Jan 22;52(2):492-501. doi: 10.1021/jm801157z.
Ying-Hong Li  1 ,  Peng Yang ,  Wei-Jia Kong ,  Yan-Xiang Wang ,  Chang-Qin Hu ,  Zeng-Yan Zuo ,  Yue-Ming Wang ,  Hong Gao ,  Li-Mei Gao ,  Yan-Chun Feng ,  Na-Na Du ,  Ying Liu ,  Dan-Qing Song ,  Jian-Dong Jiang
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 19090767 DOI: 10.1021/jm801157z
Abstract

Twenty-nine derivatives of berberine (1) or pseudoberberine (2) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. SAR analysis revealed that (i) the methylenedioxy group at the 2- and 3-position is an essential element to keep the activity, (ii) the 7-position quaternary ammonium and planar structure of the compound are activity-required, and (iii) addition of electron-donating groups at the 7- or 13-position reduced the activity. Of the compound 1 analogues, compound 2 exhibited an increased activity on LDLR expression compared to 1. In the hyperlipidemic rats, compound 2 (100 (mg/kg)/day) reduced blood CHO and LDL-c by 42.6% and 49.4%, respectively, more efficient than 1 did (p < 0.01 for both). The results were confirmed in the hyperlipidemic mice. LD(50) of 2 in mice was over 5000 mg/kg (oral). We consider compound 2 a promising cholesterol-lowering drug candidate.

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