A Comparative Study on the DNA Interactions and Biological Activities of Benzophenanthridine and Protoberberine Alkaloids

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