9-O-N-aryl/arylalkyl amino carbonyl methyl substituted berberine analogues induce self-structure in polyadenylic acid

This manuscript describes the interaction of 9-O-substituted analogues of the plant alkaloid berberine with single stranded (ss) poly(A). Three new analogues of berberine with aryl/arylalkyl amino carbonyl methyl substituents at the 9-position of the isoquinoline chromophore were evaluated for their binding to ss poly(A) by a wide variety of biophysical techniques. The results indicated that these analogues exhibited several-fold higher binding affinities than berberine. The Scatchard binding isotherms revealed that all the analogues retained the cooperative binding mode of berberine. Circular dichroism and FTIR studies unequivocally established the strong interaction potential of the analogues to ss poly(A). Optical melting and the unique dilution experiments revealed that these analogues induced self-structure formation in poly(A) and the nature of the substituent was important for the ease of formation of self-structure. Energetics of the binding suggested an entropy driven binding for the analogues in sharp contrast to the enthalpy driven binding of berberine. The introduction of the aryl/arylalkyl amino carbonyl methyl substituent thus switched the enthalpy driven binding of berberine to entropy dominated binding. Salt and temperature dependent calorimetric studies established the involvement of multiple weak noncovalent interactions in the binding process. The study also revealed that the spacer length at the 9-position had an important role in the self-structure induction.