Article

Berberine derivatives with a long alkyl chain branched by hydroxyl group and methoxycarbonyl group at 9-position show improved anti-proliferation activity and membrane permeability in A549 cells

Yi Liu1, Ke-xin Zhu2,3, Lei Cao2, Zhi-fu Xie2, Min Gu2, Wei Lü1, Jing-ya Li2, Fa-jun Nan2
1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China
2 State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Wei Lü: wlu@chem.ecnu.edu.cn, Jing-ya Li: jyli@simm.ac.cn, Fa-jun Nan: fjnan@simm.ac.cn,
DOI: 10.1038/s41401-019-0346-1
Received: 29 July 2019
Accepted: 11 November 2019
Advance online: 16 January 2020

Abstract

Berberine (BBR) exhibits diverse bioactivities, including anticancer activity; but its poor druggability limits its applications. In this study, we designed and synthesized a series of 9-O position modified BBR derivatives aiming to improve its cell permeability and anticancer activity, utilizing a long alkyl chain branched by hydroxyl group and methoxycarbonyl group. Among these compounds, B10 showed 3.6-fold higher intracellular concentration than BBR, as well as 60-fold increased anti-proliferation activity against human lung cancer A549 cells compared with BBR. Treatment with B10 (1, 2 μM) induced apoptosis of A549 cells. Further investigations showed that B10 treatment dose-dependently affected mitochondrial functions, including oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and the morphology of mitochondria in A549 cells. Therefore, this work offers a new way for BBR structural modification through improving cell membrane permeability to affect mitochondrial functions and potential anti-tumor therapy in the future.
Keywords: berberine; anticancer; membrane permeability; apoptosis; mitochondria

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