Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Isoquinoline Alkaloids as Natural Products with Unique DNA Binding Properties
Natural products of plant origin are a traditional source of medicinal compounds from time immemorial and up to forty percent of all modern drugs are essentially directly or indirectly related to natural products. Natural product drug development includes several distinct and painstaking steps like evaluation of the biological activity of plant extracts, isolation and chemical characterization of the various fractions of the extract, analysis of their structure-activity relationships, as well as elucidation of the mode and mechanism of action. One of the most important steps in these multistep processes is the elucidation of the binding of natural products to the bio-targets, like DNA/RNA/enzymes. Our laboratory has been in the forefront of elucidating the structure-activity aspects of isoquinoline alkaloids. We have successfully elucidated the mode, mechanism, base specificity and thermodynamics of DNA binding of berberine, palmatine, coralyne (protoberberine) and sanguinarine (benzophenanthridine). Berberine and palmatine showed partial intercalative mode of binding to DNA with AT base pair specificity where as coralyne and sangunarine showed intercalative binding with GC base pair specificity. Cooperativity was observed in the binding of all these alkaloids to DNA but the degree of cooperativity varied. Thermodynamically, berberine and palmatine showed entropically favorable reaction with AT rich DNA and AT polymers, while coralyne and sangunarine revealed enthalpically driven reaction in all the DNAs. These differences in the binding and energetics are probably due to the structural variations among the alkaloids as berberine and palmatine are tilted molecules while coralyne and sangunarine are planar. Parsing of the free energy change of the interaction observed into polyelectrolytic and non-polyelectrolytic components suggested that although these alkaloids are charged, the major contributor of the binding free energy arises from the non-polyelectrolytes forces. The molecular aspects on the various DNA binding properties of these alkaloids will be discussed in detail in relation to their known biological activities to give an overview of their utility for futuristic drug development.
Biophysical Chemistry Laboratory