International Journal of Molecular Sciences (2019)
Update date:2022-08-11
Topics:
Milata, Viktor
Svedova, Alexandra
Barbierikova, Zuzana
Holubkova, Eva
Cipakova, Ingrid
Cholujova, Dana
Jakubikova, Jana
Panik, Miroslav
Jantova, Sona
Brezova, Vlasta
Cipak, Lubos
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.
View Morewebsite:http://www.sagechem.com
Contact:+86-571-86818502
Address:Room C1301, New Youth Plaza, 8 Jia Shan Road, Hangzhou, China
WEIFANG RICHEM INTERNATIONAL LTD
Contact:86-536-2222176
Address:weifang,shandong
Contact:0572-2722882
Address:1201,F3,xinghuibandao,
Contact:86-536-8866010
Address:NO.4455 EAST FUSHOU ST. WEIFANG DEVELOPMENT ZONE, SHANDONG, CHINA
Tianjin Boron PharmaTech Co.,Ltd.
Contact:86-022-59845187
Address:B9-401, Tianda Science Park,No.80,4th Avenue,TEDA,Tianjin, China
Doi:10.1248/cpb1953.5.136
(1957)Doi:10.1021/ja01559a053
(1957)Doi:10.1246/bcsj.53.770
(1980)Doi:10.1002/jlcr.1614
(2009)Doi:10.1016/0022-328X(89)80080-4
(1989)Doi:10.1016/j.tetlet.2008.07.116
(2008)