Berberine C9‐Derivatives Selective Cytotoxicity Depends on Balance Between Mitochondrial Damage and DNA Intercalation

Berberine, a naturally occurring compound, inhibits the growth of cancer cells in vitro at micromolar concentrations. Selective cytotoxicity was revealed for berberine derivatives and monoterpene aminoalcohols in the FCCT (fluorescent cells co-cultivation test) screening of almost a 100 recently synthesized compounds. C9-substituted berberines were found to be selective and cytotoxic in the nanomolar concentration range, and were investigated in detail. They exhibit some selectivity for A549 and MCF7 cancer cells in comparison to non-cancerous VA13 cells. Several berberine derivatives were synthesized, which allowed us to analyze their structure-activity relationships (SAR) and mechanism of action on the cells. Investigation of berberine's and its derivatives' action on the cells revealed some similarities with DNA intercalators. Compounds bearing charged groups, such as 1 and 2, have also been observed to disrupt the mitochondrial membrane potential. Compound 17a, lacking a charge on the nitrogen, retains the effects on the cells and the ability to intercalate DNA, but affects mitochondria only at high concentrations. The significant mechanism of action of the investigated berberine derivatives is intercalation into DNA.