The structural effects and thermodynamics of the DNA binding of six berberine analogues with alkyl chains of varying length and a terminal phenyl group at the C-13 position were investigated. All the analogues bound DNA noncooperatively in contrast to the cooperative binding of berberine. The binding affinity was higher and the effect of the chain length was only up to (CH(2))(3), after which the binding affinity decreased slightly. Intercalative binding with strong stabilization of the DNA helix was revealed. Binding resulted in the weakening of the base stacking with moderate conformational changes within the B-form. The binding was entropy driven in each case, the entropy contribution to the free energy increasing with the chain length up to the threshold (CH(2))(3). The complexation was dominated by nonpolyelectrolytic forces in each case; polyelectrolytic forces contributed only a quarter to the total free energy at 50 mM [Na(+)]. Overall, the phenylalkyl substitution at the C-13 position considerably enhanced the DNA binding and was highest for the analogue with (CH(2))(3). Structural and thermodynamic data on the DNA binding aspects of the substituted berberines are presented in comparison with berberine.

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The pharmacological use of the plant alkaloid berberine is based on its antibacterial and anti-inflammatory properties; recently, anticancer activity has been attributed to this compound. To exploit this interesting feature, we synthesized three berberine derivatives, namely, NAX012, NAX014, and NAX018, and we tested their effects on two human colon carcinoma cell lines, that is, HCT116 and SW613-B3, which are characterized by wt and mutated p53, respectively. We observed that cell proliferation is more affected by cell treatment with the derivatives than with the lead compound; moreover, the derivatives proved to induce cell cycle arrest and cell death through apoptosis, thus suggesting that they could be promising anticancer drugs. Finally, we detected typical signs of autophagy in cells treated with berberine derivatives.

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Breast cancer is the most common malignancy and the most common cause of cancer death in elderly women. Chemoprevention with dietary compounds and their synthetic analogs has emerged as an attractive strategy to prevent carcinogenic progression to invasive cancer. In this study, we investigated the efficacy of some new synthetic derivatives of berberine, a phytochemical isolated from Barberry and other plants, to induce growth arrest of HER-2/neu overexpressing SK-BR-3 breast cancer cells. Supplementation with berberine or with the synthetic derivatives NAX012, NAX013, NAX014, and NAX035 exerted a dose- and time-dependent inhibition of SK-BR-3 cell viability, with a greater effectiveness of NAX012 and NAX014 compounds with respect to berberine. This cytotoxic effect was related to an increased number of apoptotic cells that reached 71.6% and 68.4% after 72 h treatment with 50 µM of NAX012 and NAX014, respectively, compared with 44.2% of berberine. Real-time PCR analyses showed that berberine, NAX012 and NAX014 compounds increased the expression of some cell-cycle checkpoint molecules involved in cell senescence such as p53, p21(WAF1) , p16(INK4a) , and PAI-1, already after 24 h of 50 µM treatments. Furthermore, berberine, NAX012 and NAX014, all reduced both HER-2/neu expression and phosphorylation on tumor cells, the NAX014 compound showing the higher effectiveness. These results provide novel information on the mechanisms involved in the anticancer effects of berberine and demonstrate the greater effectiveness of NAX012 and NAX014 analogs in inducing apoptosis and cellular senescence in HER-2/neu overexpressing tumor cell lines.