A Comparative\nStudy on the DNA Interactions and Biological\nActivities of Benzophenanthridine and Protoberberine Alkaloids

Numerous small molecules exert antitumor effects by interacting\nwith DNA, thereby influencing processes, such as DNA replication,\ntranscription, meiosis, and gene recombination. Benzophenanthridine\nand protoberberine alkaloids are known to bind DNA and exhibit many\npharmacological activities. In this study, we conducted a comparative\nanalysis of the interactions between these two classes of alkaloids\nwith G-quadruplex (G4) DNA and double-stranded DNA (dsDNA). Protoberberine\nalkaloids showed a greater affinity for binding with G4s than with\ndsDNA, while benzophenanthridine alkaloids exhibited a significantly\nstronger binding capacity for dsDNA, especially in regions that are\nrich in AT base pairs. Benzophenanthridine alkaloids also exhibited\n much stronger toxicity to various cancer cells. Compared with protoberberine\nalkaloids, benzophenanthridine alkaloids displayed much stronger\nactivity in inhibiting cellular DNA and RNA synthesis, arresting the\ncell cycle in the G2/M phase, inducing cell apoptosis, and leading\nto intracellular DNA damage. Given that dsDNA constitutes the predominant\nform of DNA within cells for the majority of the cell cycle, the significant\nantiproliferative activity of benzophenanthridine alkaloids could\nbe attributed, in part, to their higher binding affinity for dsDNA,\nthereby exerting a more significant impact on cellular proliferation.\nThese findings have valuable implications for understanding the biological\nactivities of isoquinoline alkaloids and their antitumor applications.