Synthesis of new 13-diphenylalkyl analogues of berberine and elucidation of their base pair specificity and energetics of DNA binding

A series of 13-diphenylalkyl berberine derivatives were designed and synthesized, and their base specificity and energetics of DNA binding were evaluated using one natural and two synthetic DNA polynucleotides. Biophysical evaluation demonstrated that the addition of the diphenylalkyl chain at the 13-position of berberine significantly improved the binding ability to DNA. The binding clearly revealed the high preference of the analogues to the alternating AT sequences compared to the alternating GC sequences. The binding affinity was enhanced with the increase in chain length up to a critical length of (CH2)(3) in all the cases, after which the binding affinity decreased. Analogue BR4 had the best affinity for DNA, which corresponds to a length of (CH2)(3). The results also suggested the adenine-thymine (AT) base specificity of these berberine analogues and that the length of the side chain at the 13-position of the isoquinoline chromophore is critical in modulating the binding affinity.