The development of small-molecules which target nucleic acids, more specifically the minor groove of DNA, in a sequence specific manner and control gene expression are currently being investigated as potential therapeutic compounds for the treatment of various diseases, including cancer, as well as viral and bacterial infections. The naturally occurring compounds netropsin and distamycin have been shown to demonstrate antitumor and antibacterial properties. Currently, there are synthetic efforts to create pyrrole and imidazole-containing polyamide derivatives of netropsin and distamycin that show potential as medicinal agents. Synthetic pyrrole and imidazole-containing polyamides are potentially useful for targeting and modulating the expression of genes, including those associated with cancer cell growth. The key challenges that must be overcome to realize this goal of using synthetic polyamides in the treatment of disease are the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have appreciable water solubility, bind DNA sequence specifically, and with high affinity. As part of a systematic study within the authors’ laboratory, our goal is to develop polyamides which can be synthesized readily yet possess excellent sequence specificity, stronger binding affinity, high solubility in biological media and enhanced cell penetration and nuclear localization properties. There is a need to develop a library of modified polyamides which target DNA and exhibit improved biological properties. The present study is a systematic examination of the binding properties of various modified synthetic polyamide compounds. The synthetic polyamide derivatives presented have more potential as therapeutic candidates over other synthetic polyamides because of their increased water solubility, smaller molecular weights, and molecular design, thus, allowing them to penetrate into cells and localize in the nucleus.

One electron oxidation of DNA has been studied extensively over the years. When a charge is injected into a DNA duplex, it migrates through the DNA until it reaches a trap. Upon further reactions, damage occurs in this area and strand cleavage can occur. Many works have been performed to see what can affect this damage to DNA. Netropsin is a minor groove binder that can bind to tracts of four to five A:T base pairs. It has been used in the studies within to determine if it can protect DNA against oxidative damage, caused by one-electron oxidation, when it is bound within the minor groove of the DNA. By using a naphthacenedione derivative as a photosensitizer, several DNA duplexes containing netropsin binding sites as well as those without binding sites, were irradiated at 420 nm, analyzed, and visualized to determine its effect on oxidative damage. It has been determined netropsin creates a quenching sphere of an average of 5.8 * 108 Šwhether bound to the DNA or not. Herein we will show netropsin protects DNA against oxidative damage whether it is free in solutions or bound within the minor groove of a DNA duplex.