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Caught in the oxirane: Naphthalene diimides conjugated to a quinone methide and an oxirane have been synthesized and investigated as selective DNA G-quadruplex alkylating agents. The oxirane derivative generates a stable adduct with a G-quadruplex and shows selective alkylation of the loop adenines, as illustrated

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.

Abstract. naphthalene diimide (nDi) derivatives have shown high affinity for telomeric guanine (G)-quadruplexes and good antiproliferative activity in different human tumor experimental models. A trisubstituted compound (H-NDI-NMe 2 ) has been reported to stabilize the telomeric G-quadruplex and to cause telomere dysfunction and downregulation of telomerase expression. We further investigated its mechanism of action by analyzing the capability of the molecule to interfere with the expression levels of oncogenes, such as MYC, telome rase reverse transcriptase (TERT), KIT and BCL2, known to bear G-quadruplex-forming sequences within their promoters, in human tumor cell lines of different histological origin. Exposure to H-NDI-NMe 2 resulted in a cell type-dependent perturbation of the expression levels of the four selected genes. Biophysical and molecular analyses revealed that H-NDI-NMe 2 bound with high affinity and effectively stabilized mainly MYC and BCL2, which share long sequences and the possibility of multiple G-quadruplex folding. The mRNA levels of both genes, but not protein amounts were affected by NDI treatment. Global gene expression analysis showed modulation of genes implicated in telomere function and mechanisms of cancer; however, G-quadruplex-mediated regulation of gene expression by H-NDI-NMe 2 was largely dependent on the cell context. These data indicate that a deeper knowledge on the molecular mechanisms and biological effects of G-quadruplex structures is still needed to help developing new effective anticancer agents.

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