Berberine is one of the most widely known alkaloids belonging to the protoberberine group
exhibiting myriad therapeutic properties. The anticancer potency of berberine appears to derive from
its multiple actions including strong interaction with nucleic acids exhibiting adenine-thymine base
pair specificity, inhibition of the enzymes topoisomerases and telomerases, and stabilizing the
quadruplex structures. It was realized that the development of berberine as a potential anticancer agent
necessitates enhancing its nucleic acid binding efficacy through appropriate structural modifications.
More recently a number of such approaches have been attempted in various laboratories with great
success. Several derivatives have been synthesized mostly with substitutions at the 8, 9 and 13 positions of the
isoquinoline chromophore, and studied for enhanced nucleic acid binding activity. In this article, we present an up to date
review of the details of the interaction of berberine and several of its important synthetic 8, 9 and 13 substituted
derivatives with various nucleic acid structures reported recently. These studies provide interesting knowledge on the
mode, mechanism, sequence and structural specificity of the binding of berberine derivatives and correlate structural and
energetic aspects of the interaction providing better understanding of the structure- activity relations for designing and
development of berberine based therapeutic agents with higher efficacy and therapeutic potential.
Keywords: Berberine analogs, binding, nucleic acids, specificity, therapeutic potential.
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