22 DNA-Binding Radioprotectors

For decades the world of radioprotectors has been dominated by the aminothiols, in particular WR1065 and its prodrug amifostine. These drugs emerged from an extensive programme of synthesis and evaluation under the auspices of the Walter Reed Army Institute of Research starting in the early 1950s (Sweeny, 1979). As discussed in detail in section 4 below, structure-activity studies on a series of aminothiols in John Ward’s lab at the University of San Diego established a relationship between net charge and radioprotective activity. Positive charge conferred a DNA binding capability, by ionic interaction, and improved radioprotective activity. This was consistent with the fact that an important aspect of the mechanism of radioprotection by WR1065 is its radical scavenging activity. Given the limited range of diffusion of hydroxyl radicals generated from ionisation of water molecules, it makes sense that the radical scavengers will be most effective when located in the close vicinity of DNA. This basic rationale prompted the synthesis and evaluation of an aminothiol tethered to a DNA intercalating agent (Laayoun et al., 1994), but there is no evidence in the literature of a systematic follow-up. Also, the new DNA binding radioprotector methylproamine emerged not from a rational design premise, but rather, from the serendipitous discovery of radioprotective activity of a minor groove binder Hoechst 33342 synthesized by the Hoechst company as part of a program aimed at developing antihelminthics. From that starting point, a modest lead optimisation program guided by a mechanistic hypothesis showed that radioprotective activity was enhanced by the introduction of more electron-rich substituents into the phenyl ring of the molecule. Thus, this article links two groups of radioprotectors with the common feature of DNAbinding, albeit with quite different affinities. The dissociation constant for the WR1065-DNA interaction is in the mM range (Smoluk et al., 1986), whereas that for methylproamine is a few hundred nM (Martin et al., 2004). Accordingly, the relative radioprotective potency of WR1065 and methylproamine differs by more than 2-orders of magnitude. In contrast to this focus, other publications review a much wider range of radioprotectors (Hosseinimehr, 2007; Weiss & Landauer, 2009; Citrin, 2010).