Summary Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15% 1. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras 2. p53 is also frequently inactivated in NSCLC and, since oncogenic Ras can be a potent trigger of p53 3, it seems likely that oncogenic Ras signalling plays a major and persistent part in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease 4. Here, we model the likely therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras 5. Surprisingly, p53 restoration failed to induce significant regression of established tumours although it did result in a significant decrease in the relative proportion of tumours classed as high grade. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked up regulation in Ras signal intensity and induction of the oncogenic signalling sensor p19ARF 6. Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and to the efficacy of therapeutic p53 restoration to eradicate cancers.

The synthesis and structural characterization of a new pro-chelating agent, isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide (BSIH), are presented. BSIH only weakly interacts with iron unless hydrogen peroxide (H2O2) is present to remove the boronic ester protecting group to reveal a phenol that is a key metal-binding group of tridentate salicylaldehyde isonicotinoyl hydrazone (SIH). BSIH prevents deoxyribose degradation caused by hydroxyl radicals that are generated from H2O2 and redox-active iron by sequestering Fe3+ and preventing iron-promoted hydroxyl radical formation. The rate-determining step for iron sequestration is conversion of BSIH to SIH, followed by rapid Fe3+ complexation. The pro-chelate approach of BSIH represents a promising strategy for chelating a specific pool of detrimental metal ions without disturbing healthy metal ion distribution.

Manipulation of weak intermolecular interactions guides the rational design [1] of sensors, drugs, and foldamers-synthetic, [2] nonnatural backbones that fold into an ordered, biomimetic array. 1,4-Substituted 1,2,3-triazoles, which are readily accessible through the Cu I -catalyzed Huisgen 1,3-dipolar cycloaddition of azides and alkynes, [3] are seemingly universal ligation tools [4] whose capacity for independent function has received far less attention. Recent reports, however, indicate that the size and dipole moment ( % 5 D) of triazoles make them interesting candidates for amide bond surrogates, [5] and Arora and co-workers have reported the contributions of triazoles to the conformational preferences of peptidotriazole oligomers. [6] We hypothesized that oligomer 1 would fold in a manner similar to other linear, flexible oligomers [7] to provide a model cavity by which to explore the intermolecular interactions between the electropositive CH side of 1,4-triazoles and electron-rich guests such as anions ( Figure 1). Our expectations were buoyed by previous reports of anion-induced folding, [8,9] in particular by a recent demonstration by Jeong and co-workers [8] that the folding of oligoindoles can be directed through a helical arrangement of NH···anion hydrogen bonds. Herein, we report 1) that 1:1 interactions between diaryl triazoles and chloride ions in acetone are directional and sufficiently strong as to be observable by 1 H NMR spectroscopy, 2) that the strength of the interaction increases with the generation of triazole-containing oligomer, and 3) that CH···anion contacts guide the folding of aryl triazole oligomers in solution and in the solid state.While the "click" coupling of alkyl azides with alkynes is highly efficient, [10] the formation of diaryl triazoles has, until recently, been relatively more difficult and less efficient. [11] Nonetheless, under modified conditions, the Cu I -catalyzed cycloaddition produces acceptable yields of the desired 1,4-diaryl-1,2,3-triazole-containing compounds 1-3. A tetraethylene glycol unit was introduced outside of the cavity for solubility.Oligomer 1 has appreciable conformational freedom only around the arene-triazole single bonds. Molecular modeling [12] suggested no significant preference for a particular rotamer, a prediction that is supported by NOESY spectra of 1 in [D 6 ]acetone (Figure 2 a). Modeling studies also show that complexation of 1 with Cl À aligns the electropositive triazole CH units toward the interior of a helix, within which the Cl À is bound.The computer modeling holds true in solution, where the chloride-induced folding of 1 is revealed by 1 H NMR spectroscopy. The 1 H NMR spectrum of 1 changes considerably upon the addition of tetrabutylammonium chloride