DNA-binding properties of nitroarene oligopeptides designed as hypoxia-selective agents

The DNA-binding properties of six candidate nitroarene-functionalized oligopeptides 8-13 (i.e. 5-nitrofuran, 2-nitroimidazole and 4-nitrobenzene derivatives) with potential hypoxia-selective activity, developed as analogues of the archetypal minor groove-binding ligands, netropsin 1 and distamycin 2, have been examined using an extended molecular mechanics and dynamics (MM/MD) modelling approach. The energies calculated for interaction with the d(CGCGAATTCGCG) duplex, or d(CGCAAATTTGCG)2 in the case of the elongated nitrobenzene 13, correlate with fluorimetric data obtained by indirect competitive displacement of ethidium bromide from double-stranded calf thymus DNA. The results suggest that the mode of interaction for these agents resembles the behavior of structurally unrelated bis(amidine) derivatives that also bind to AT-rich stretches of duplex B-DNA via the minor groove. Analysis of the binding behaviour indicates that the interactions are determined by enthalpic rather than entropic energy terms, suggesting that specific or differential hydration effects for the DNA and ligand may be unimportant. A rational structure-activity relationship is established for the interaction of this family of oligopeptides with DNA that also encompass the bis(amidine) class of ligands.