Synthesis and Anticancer Activity of Novel 9-O-Substituted Berberine Derivatives

Abstract

Berberine is a bioactive isoquinoline alkaloid derived from many plants. Although berberine has been shown to inhibit growth and induce apoptosis of several tumor cell lines, its poor absorption and moderate activity hamper its full therapeutic potential. Here, we describe the synthesis of a series of 9-O-substituted berberine derivatives with improved antiproliferative and apoptosis-inducing activities. An analysis of novel berberine derivatives by EPR spectroscopy confirmed their similar photosensitivity and analogous behavior upon UVA irradiation as berberine, supporting their potential to generate ROS. Improved antitumor activity of novel berberine derivatives was revealed by MTT assay, by flow cytometry and by detection of apoptotic DNA fragmentation and caspase-3 activation, respectively. We showed that novel berberine derivatives are potent inhibitors of growth of HeLa and HL-60 tumor cell lines with IC50 values ranging from 0.7 to 16.7 µM for HL-60 cells and 36 to >200 µM for HeLa cells after 48 h treatment. Further cell cycle analysis showed that the observed inhibition of growth of HL-60 cells treated with berberine derivatives was due to arresting these cells in the G2/M and S phases. Most strikingly, we found that berberine derivative 3 (9-(3-bromopropoxy)-10-methoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a] isoquinolin-7-ylium bromide) possesses 30-fold superior antiproliferative activity with an IC50 value of 0.7 µM and 6-fold higher apoptosis-inducing activity in HL-60 leukemia cells compared to berberine. Therefore, further studies are merited of the antitumor activity in leukemia cells of this berberine derivative.

Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents

“…In addition, a recent study reported various analogs of berberine on the 9-/13-position using different chain lengths and terminal amino groups were synthesized and evaluated on the DNA-binding affinity or as G-quadruples stabilizing ligands [23][24][25][26]. The study also showed the introduction of a lipophilic substituent into the 9-O-position of the berberine backbone and enhanced the anti-proliferative activities against human cancer cell lines [27][28][29][30]. However, structural modification on the 13-position of the berberine backbone has rarely been reported [31].…”

Dechloromethylation of the berberine to berberrubine — tricks to obtain pure product

“…It behaves as a fluorescent chemosensor of alkanes with an almost constant response regardless of the alkane chain length (Delgado-Camón, 2015). Because many biological activities are related to structural modifications (Xiao, 2017) at position 9 (Liu, 2017, Xiao 2018, some 9-substituted derivatives were prepared (Milata, 2019). Dechloromethylation of the starting berberine (1) selectively occurring at position 9 is the key step leading to derivatization of this position.…”

Antimetastatic and Antitumor Activities of Orally Administered NAX014 Compound in a Murine Model of HER2-Positive Breast Cancer

“…However, issues related to BBR poor bioavailability and toxicity may limit its translation to clinical trials. New compounds obtained by chemical manipulation of the parental molecule provide a source of promising chemotherapeutic or chemo-preventive agents [ 15 , 16 , 17 ]. Nevertheless, preclinical evidences of antitumor efficacy of BBR-derivatives are scarce or absent for most of them.…”