Antitumour activity of the novel flavonoid Oncamex in preclinical breast cancer models.

BACKGROUND: The natural polyphenol myricetin induces cell cycle arrest and apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with enhanced redox properties, improved cell uptake and mitochondrial targeting might have increased potential as antitumour agents. METHODS: We studied the effect of a second-generation flavonoid analogue Oncamex in a panel of seven breast cancer cell lines, applying western blotting, gene expression analysis, fluorescence microscopy and immunohistochemistry of xenograft tissue to investigate its mechanism of action. RESULTS: Proliferation assays showed that Oncamex treatment for 8 h reduced cell viability and induced cytotoxicity and apoptosis, concomitant with increased caspase activation. Microarray analysis showed that Oncamex was associated with changes in the expression of genes controlling cell cycle and apoptosis. Fluorescence microscopy showed the compound's mitochondrial targeting and reactive oxygen species-modulating properties, inducing superoxide production at concentrations associated with antiproliferative effects. A preliminary in vivo study in mice implanted with the MDA-MB-231 breast cancer xenograft showed that Oncamex inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no signs of untoward effects on the animals. CONCLUSIONS: Oncamex is a novel flavonoid capable of specific mitochondrial delivery and redox modulation. It has shown antitumour activity in preclinical models of breast cancer, supporting the potential of this prototypic candidate for its continued development as an anticancer agent.

Series of quinone-containing nanosensors for biologically relevant redox potential determination by surface-enhanced Raman spectroscopy.

Redox potential is of key importance in the control and regulation of cellular function and lifecycle, and previous approaches to measuring the biological redox potential noninvasively in real time are limited to areas of hypoxia or normoxia. In this paper, we extend our previous work on nanoparticle-based intracellular nanosensors to cover a much wider redox potential range of -470 to +130 mV vs NHE, which includes the redox potential range occupied by cells in a state of oxidative stress. The nanosensors are rationally designed to target different areas of this redox potential range and are monitored by surface-enhanced Raman spectroscopy, which will permit noninvasive real-time imaging of cells undergoing oxidative stress.

AAAA-DDDD quadruple hydrogen-bond arrays featuring NH···N and CH···N hydrogen bonds.

The X-ray crystal structure of a previously reported extremely strong quadruple NH···N AAAA-DDDD hydrogen-bond array [5·4] (K(a) = 1.5 × 10(6) M(-1) in CH3CN; K(a) > 3 × 10(12) M(-1) in CH2Cl2) features four short linear hydrogen bonds. Changing the two benzimidazole groups of the DDDD unit to triazole groups replaces two of the NH···N hydrogen bonds with CH···N interactions (complex [5·6]), but only reduces the association constant in CH3CN by 2 orders of magnitude (K(a) = 2.6 × 10(4) M(-1) in CH3CN; K(a) > 1 × 10(7) M(-1) in CH2Cl2). Related complexes without the triazole groups range in K(a) from 18 to 270 M(-1) in CH3CN, suggesting that the CH···N interactions can be considered part of a strong AAAA-DDDD quadruple hydrogen-bonding array. The NH···N/CH···N AAAA-DDDD motif can be repeatedly switched "on" and "off" in CDCl3 through successive additions of acid and base.

An AAAA­DDDD quadruple hydrogen-bond array.

Secondary electrostatic interactions between adjacent hydrogen bonds can have a significant effect on the stability of a supramolecular complex. In theory, the binding strength should be maximized if all the hydrogen-bond donors (D) are on one component and all the hydrogen-bond acceptors (A) are on the other. Here, we describe a readily accessible AAAA­DDDD quadruple hydrogen-bonding array that exhibits exceptionally strong binding for a small-molecule hydrogen-bonded complex in a range of different solvents (K(a) > 3 × 10(12) M(-1) in CH2Cl2, 1.5 × 10(6) M(-1) in CH3CN and 3.4 × 10(5) M(-1) in 10% v/v DMSO/CHCl3). The association constant in CH2Cl2 corresponds to a binding free energy (ΔG) in excess of ­71 kJ mol(-1) (more than 20% of the thermodynamic stability of a carbon­carbon covalent bond), which is remarkable for a supramolecular complex held together by just four intercomponent hydrogen bonds.