| The DNA minor groove continues to be an important target for the development of anticancer, antiviral, and antimicrobial compounds. Studies of benzimidazole-DNA binders have made it clear that the benzimidazole-amidine portion of these molecules drives an efficient and site-selective DNA association. We sought to augment the activity of benzimidazoles through their conjugation to amino acids. Accordingly, a new series of DNA minor groove binding agents based on benzimidazole-amino acid conjugates was designed and synthesized, and their DNA binding was investigated by an FID assay. In this design, the benzimidazole-amidine portion of the molecule was used as a core structure, and different amino acids were introduced into the structure to form a series of amino acid-benzimidazole-amidine conjugates. To obtain these structures, a new, efficient solid-phase synthesis protocol was developed as well. To determine the binding affinity and selectivity of these compounds among all possible 4-base pair sequences of DNA, a high throughput (HT), fluorescence intercalator displacement (FID) assay was employed.;The FID results indicate that these compounds are good DNA minor groove binders as predicted (more than 50% fluorescence decrease at 10 muM for A/T only sequences); the amidine group improves the binding affinity and selectivity compared to amino acid-benzimidazole conjugates without an amidine group; the amino acid can improve the binding affinity further. |
