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A non-fluorescent naphthalene diimide (NDI) dimer, conjugating red and blue NDI dyes, becomes red/NIR emitting upon G-quadruplex binding. The fluorescence lifetime which is significantly different for the complexes, the G-quadruplex/dimer and the weakly emitting ds-DNA/dimer is the key feature for the development of new rationally engineered G-quadruplex sensors. [ABSTRACT FROM AUTHOR]

Computational chemistry has come of age in drug discovery. Indeed, most pharmaceutical development programs rely on computer-based data and results at some point. Herein, we discuss recent applications of advanced simulation techniques to difficult challenges in drug discovery. These entail the characterization of allosteric mechanisms and the identification of allosteric sites or cryptic pockets determined by protein motions, which are not immediately evident in the experimental structure of the target; the study of ligand binding mechanisms and their kinetic profiles; and the evaluation of drug-target affinities. We analyze different approaches to tackle challenging and emerging biological targets. Finally, we discuss the possible perspectives of future application of computation in drug discovery., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The syntheses and investigations of new biologically active derivatives of dihydropyrimidines by Biginelli reaction in the presence of copper triflate are reported. Due to the fact that salicylaldehyde and its derivatives under Biginelli reaction conditions can lead to the formation of 2 types of dihydropyrimidines, the influence of copper triflate on product formation was also investigated. In addition to this, regioselective oxidation of dihydropyrimidines was performed in the presence of cerium ammonium nitrate and novel oxidized dihydropyrimidines were obtained. Single crystals of some of them were obtained and as a result, the structures of them were investigated by X-ray diffraction method, which allows determining the presence of hydrogen bonds in their structures. In addition to this, the presence of hydrogen bonds in their structures affects the formation of the corresponding tautomer during oxidizing of dihydropyrimidines. Since dihydropyrimidines are claimed to be biologically active compounds, activities of the synthesized compounds were studied against Acinetobacter baumanii , Escherichia coli , Pseudomonas aeruginosa , Klebsiella pneumoniae and Staphylococcus aureus bacteria., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

We report on the potential of a water-soluble tetracationic quaternary ammonium naphthalene diimide (NDI) as multifunctional agent of interest for theranostic applications. The DNA binding ability of this NDI has been investigated. NDI exhibits high binding constants for G-quadruplex DNA but it is not selective for this type of DNA. Taking advantage of its intrinsic fluorescence and singlet oxygen sensitizing ability, cellular uptake, cytotoxicity and photocytotoxicity have been investigated. The intense emission in the red/NIR allows monitoring of the cell permeability of this charged tetracationic NDI, accumulating into the cell nuclei. No dark cytotoxicity has been observed on selected tumor cell lines. Irradiation of the NDI loaded cells with red light reduces cell viability up to 40% and causes a significant increase of the percentage of cells expressing γH2AX foci indicating DNA damage. The presence of distinct DNA damage foci inside the nucleus suggests that the NDI molecule might induce DNA damage in specific sites. To the best of our knowledge this is the first NDI exhibiting PDT activity at μM concentration combined with low dark cytotoxicity.

A small library of hydrosoluble naphthalene diimides (NDIs) was designed and synthesized, as cell permeable pH "turned-on" fluorescent sensors, for cellular applications. The NDIs exhibit a non-emitting twisted intramolecular charge transfer (TICT) state, which has been described by a DFT computational investigation. These NDIs do not emit as a free base, but they become strong emitters when protonated. Switching of the red emission was achieved in the pH window 2.5-6, tuning steric and electronic features of the amine moiety. The least acidic protonated NDI (pKa 5.1), was investigated in normal and cancer cells. Its selective redistribution in cancer cells from acidic vesicular organelles to the cytoplasm and the nucleus describes an effective application of these NDIs as a valuable functional tool.

Aryl ethynyl anthraquinones have been synthesized by Sonogashira cross-coupling and evaluated as telomeric G-quadruplex ligands, by the FRET melting assay, circular dichroism, the DNA synthesis arrest assay and molecular docking. Both the binding properties and G-quadruplex vs. duplex selectivity are controlled by the structures of the aryl ethynyl moieties.

Mimicking biochromophore anions containing phenolate moieties, eight conjugated naphthalene diimides (NDIs) have been synthesized in order to develop probes, displaying charge-transfer transitions affected by the nearby environment. NIR absorption of the resulting phenolates and their solvatochromic properties in both organic solvents and water are described.

Extended naphthalene diimides (NDIs) fused to 1,4-dihydropyrazine-2,3-dione, containing two solubilizing moieties, have been synthesized. Fluorescence spectra of the new NDIs were remarkably affected by pH, as the second deprotonation of the dihydropyrazinedione moiety (pK(a) 6.9) switched off the emission. Binding to a G-quadruplex folded oligonucleotide and stoichiometry were evaluated by FRET melting assay and CD analysis. G-quadruplex binding was strongly enhanced shifting from pH 7.4 to pH 6.0 as a consequence of the dihydropyrazinedione moiety protonation. Cytotoxicity studies using two human telomerase-positive cell lines (HT29 and A549) revealed that the best G-quadruplex ligand was very active against the colon cell line, with an EC(50) of 300 nM.

The synthesis, physico-chemical properties and biological effects of a new class of naphthalene diimides (NDIs) capable of reversibly binding telomeric DNA and alkylate it through an electrophilic quinone methide moiety (QM), are reported. FRET and circular dichroism assays showed a marked stabilization and selectivity towards telomeric G4 DNA folded in a hybrid topology. NDI-QMs' alkylating properties revealed a good reactivity on single nucleosides and selectivity towards telomeric G4. A selected NDI was able to significantly impair the growth of melanoma cells by causing telomere dysfunction and down-regulation of telomerase expression. These findings points to our hybrid ligand-alkylating NDIs as possible tools for the development of novel targeted anticancer therapies., (This journal is © The Royal Society of Chemistry 2012)

The photoactivation of 6,6'-bis-CH2X-[2,2']bipyridinyl-5,5'-diol ligands as mono and bis-alkylating agents has been investigated, detecting transient heterocyclic quinone methides.

A novel approach towards quinone methides stabilization has been achieved by anchoring the reactive o-QM intermediate on solid phase (RTHP). The reactivity and selectivity of supported o-QM towards N and S centered nucleophiles have been explored.