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

Abstract

The objective of this study was to synthesize the 9-/13-position substituted berberine derivatives and evaluate their cytotoxic and photocytotoxic effects against three human cancer cell lines. Among all the synthesized compounds, 9-O-dodecyl- (5e), 13-dodecyl- (6e), and 13-O-dodecyl-berberine (7e) exhibited stronger growth inhibition against three human cancer cell lines, (HepG2, HT-29 and BFTC905), in comparison with structurally related berberine (1). These three compounds also showed the photocytotoxicity in human cancer cells in a concentration-dependent and light dose-dependent manner. Through flow cytometry analysis, we found out a lipophilic group at the 9-/13-position of berberine may have facilitated its penetration into test cells and hence enhanced its photocytotoxicity on the human liver cancer cell HepG2. Further, in cell cycle analysis, 5e, 6e, and 7e induced HepG2 cells to arrest at the S phase and caused apoptosis upon irradiation. In addition, photodynamic treatment of berberine derivatives 5e, 6e, and 7e again showed a significant photocytotoxic effects on HepG2 cells, induced remarkable cell apoptosis, greatly increased intracellular ROS level, and the loss of mitochondrial membrane potential. These results over and again confirmed that berberine derivatives 5e, 6e, and 7e greatly enhanced photocytotoxicity. Taken together, the test data led us to conclude that berberine derivatives with a dodecyl group at the 9-/13-position could be great candidates for the anti-liver cancer medicines developments.

Berberine Derivatives Suppress Cellular Proliferation and Tumorigenesis In Vitro in Human Non-Small-Cell Lung Cancer Cells

“…Our previous report demonstrated the absorption and emission spectra of 9- O -dodecylberberrubine bromide (B7) are 420 nm and 529 nm in the cells [ 6 ]. In the present study, we confirm this phenomenon for B6 and B7 in A549 and H1435 cells after incubation.…”

“…Moreover, berberine has been demonstrated to be a safety agent for cancer therapy [ 10 ]. In our previous study, we generated a series of compounds from berberine with 9-position-substituted derivatives B2 to B7, which exert better anti-cancer behavior than berberine in human hepatoma, colon and bladder cancer cells [ 6 ]. Here, we demonstrated that berberine derivatives, including 9- O -hexylberberrubine bromide (B4), 9- O -octylberberrubine bromide (B5), 9- O -decylberberrubine bromide (B6), and 9- O -dodecylberberrubine bromide (B7), have better anti-NSCLC activity than berberine (B1) ( Figure 2 and Table 1 ).…”

“…A previous study reported that berberine and its derivatives could be taken up by cancer cells, and they could be excited with a wavelength of 420 nm and emit wavelengths of 529 to 531 nm [ 6 ]. Moreover, they show photocytotoxicity in hepatoma, colon and bladder cancer cells [ 6 ]. We also confirmed that B6 and B7 could emit green fluorescence under excitation with 488 nm ( Figure 7 ).…”

“…Our previous study demonstrated that an S phase arrest was observed in the cells incubated with berberine and its derivatives after exposure to irradiation (420 nm) [ 6 ]. Moreover, cellular apoptosis was elevated under this condition.…”

“…Previously, we synthesised a series of berberine derivatives, including 9- O -alkyl-, 13-alkyl- and 13- O -alkylberberine bromide, and evaluated their potential anti-cancer ability in human hepatoma, colon cancer and bladder cancer cell lines [ 6 , 7 ]. We demonstrated that these compounds exhibit stronger proliferation inhibition properties than berberine [ 6 , 7 ]. However, the mechanisms of these berberine derivatives against human hepatoma, colon cancer and bladder cancers are still unclear.…”