Synthesis and Anticancer Activity of Novel 9-O-Substituted Berberine Derivatives
Abstract
:1. Introduction
2. Results and Discussion
3. Materials and Methods
3.1. Experimental Methods
3.1.1. Chemistry
General
Selective Demethylation of Berberine on Its C9 Position
Synthesis of 9-(2-Chloro- or Bromo-acetoxy)-10-metoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a] isoquinoline-7-ylium Chloride or Bromide
Synthesis of 9-(3-Bromopropoxy)-10-methoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a] isoquinolin-7-ylium Bromide
Synthesis of 1-Cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carbonyl Chloride
Synthesis of 9-(1-Cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydroquinoline-3-carbonyloxy)-10-methoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium Chloride
3.1.2. Electron Paramagnetic Resonance (EPR) Spectroscopy Studies of Berberine Derivatives
3.1.3. Evaluation of Antiproliferative Activities of Berberine Derivatives
Cell Cultures and Determination of Cell Viability and Morphology
Detection of Induction of Apoptosis by DNA Laddering Assay
Detection of Apoptosis by Caspase-3 Assay
Determination of Cell Cycle Distribution
Author Contributions
Funding
Conflicts of Interest
Abbreviations
DBP | 1,3-Dibromopropane |
DMF | Dimethylformamide |
DMPO | 5,5-Dimethyl-1-pyrroline N-oxide |
DMSO | Dimethyl Sulfoxide |
DTT | Dithiothreitol |
MTT | 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
PBS | Phosphate buffer saline |
PI | Propidium iodide |
ROS | Reactive Oxygen Species |
RT | Room temperature |
Tempone | 4-Oxo-2,2,6,6-tetramethylpiperidine N-oxyl |
THF | Tetrahydrofuran |
TMPO | 4-Oxo-2,2,6,6-tetramethylpiperidine |
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Reaction | DBP (Equivalents) | Solvent | Temperature (°C) | Time (h) | Yield (%) |
---|---|---|---|---|---|
R1 | 3 | CH3CN | 60 | 2 | 48 |
R2 | 10 | CH3CN | 60 | 2 | 55 |
R3 | 10 | DMF | 80 | 2 | 59 |
R4 | 58 | DMF | 80 | 2 | 74 |
Cell Line | Time (h) | Berberine | Ciprofloxacin | 1 | 2 | 3 | 4 |
---|---|---|---|---|---|---|---|
HeLa | 24 | ˃200 | ˃200 | ˃200 | ˃200 | 58 ± 2.6 | ˃200 |
48 | 126 ± 7.8 | 175 ± 8.7 | 115 ± 7.4 | 95 ± 4.8 | 36 ± 1.9 | ˃200 | |
HL-60 | 24 | 43.7 ± 1.1 | ˃200 | 23.4 ± 2.6 | 14.6 ± 1.7 | 2.7 ± 0.9 | 19.3 ± 1.3 |
48 | 27.1 ± 2.6 | 142 ± 5.7 | 16.7 ± 0.8 | 11.2 ± 1.6 | 0.7 ± 0.2 | 15.7 ± 1.9 |
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Milata, V.; Svedova, A.; Barbierikova, Z.; Holubkova, E.; Cipakova, I.; Cholujova, D.; Jakubikova, J.; Panik, M.; Jantova, S.; Brezova, V.; et al. Synthesis and Anticancer Activity of Novel 9-O-Substituted Berberine Derivatives. Int. J. Mol. Sci. 2019, 20, 2169. https://doi.org/10.3390/ijms20092169
Milata V, Svedova A, Barbierikova Z, Holubkova E, Cipakova I, Cholujova D, Jakubikova J, Panik M, Jantova S, Brezova V, et al. Synthesis and Anticancer Activity of Novel 9-O-Substituted Berberine Derivatives. International Journal of Molecular Sciences. 2019; 20(9):2169. https://doi.org/10.3390/ijms20092169
Chicago/Turabian StyleMilata, Viktor, Alexandra Svedova, Zuzana Barbierikova, Eva Holubkova, Ingrid Cipakova, Dana Cholujova, Jana Jakubikova, Miroslav Panik, Sona Jantova, Vlasta Brezova, and et al. 2019. "Synthesis and Anticancer Activity of Novel 9-O-Substituted Berberine Derivatives" International Journal of Molecular Sciences 20, no. 9: 2169. https://doi.org/10.3390/ijms20092169