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Hybrid ligand–alkylating agents targeting telomeric G-quadruplex structures

Dipartimento di Chimica, Università di Pavia, V.le Taramelli 10, 27100 Pavia, Italy.
Organic & Biomolecular Chemistry (Impact Factor: 3.49). 02/2012; 10(14):2798-806. DOI: 10.1039/c2ob06816h
Source: PubMed

ABSTRACT 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.

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    • "Nevertheless, there are several other classes of indirect telomerase inhibitors characterized by a remarkable chemical diversity, such as porphyrins, perylene diimides, fluoroquinolones, indoloquinolines , cryptolepines, quindolines, phenanthrolines, triazines, carbazole derivatives, ethidium derivatives, bisamido-anthraquinones , fluorenones, acridones and acridines [29]. Recently, a new class of naphthalene diimides (NDIs), capable of reversibly binding and subsequently alkylating telomeric DNA, has been identified [30]. Phenanthroline derivatives and pyridostatin have been used in several cell-culture studies, in which they have been demonstrated to bind within the cells and disrupt the expression of targeted DNA-quadruplex-forming sequences [31-33]. "
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    ABSTRACT: G-quadruplexes (G4) are non-canonical DNA structures assumed by guanine rich sequences. G4 are stabilized by the presence of cations and are characterized by a high degree of structural polymorphism with different patterns of groove, loop arrangement, strand orientations and stoichiometry. G-rich sequences are over-represented in the promoter regions of many oncogenes as well as at human telomeres, d(TTAGGG) repeats, ranging in size from 3 to 15 kb, involved in protecting chromosomal ends. A specialized enzyme, called telomerase, provides a telomere maintenance mechanism by elongating the end of the G-strand and it is activated in the majority of cancer cells. Therefore there are two general strategies of telomerase targeting in cancer treatment. One is a direct targeting of telomerase to cause its inhibition; the other one is the use of G4 stabilizers which block telomerase access to telomere, thus causing an indirect enzyme inhibition. Here, we evaluated the molecular recognition of some phenanthroline-based ligands against four different experimental models of the human telomeric sequence d[AG3(T2AG3)3] by means of docking simulations. Our theoretical analysis was able to reproduce the experimental affinity measurements, with a linear squared correlation factor r2 equal to 0.719 among all the studied models. These findings highlighted the importance to consider the polymorphism of the DNA G4. Interestingly, this correlation resulted always improved with respect to that of the single folds, with the exception of the parallel structure, thus suggesting a key role of this G4 conformation in the interaction network of the tested binders. Moreover, we identified the moieties of the phenanthroline scaffold directly involved in the complex formation. This allowed to rationalize the improved binding affinity always associated with a bis-phenanthroline system and to explain why a phenanthroline substituted with a pyridine ring is favored with respect to the pyrimidine one.
    Open Journal of Medicinal Chemistry 06/2013; 3(2):41-49. DOI:10.4236/ojmc.2013.32006
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    • ") . NDs could also be used for targeting stromal and cancer stem cells for their ability to induce DNA damage and senescence . The ND compounds discussed here appear to be significantly more potent antiproliferative agents than others that have been pre - viously reported ( see , e . g . , Nadai et al . , 2011 ; Doria et al . , 2012a , b ; Wang et al . , 2012 ) , possibly as a result of their superior quadruplex - binding ability , although detailed mech - anistic studies have not as yet been reported for these other ND compounds ."
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    ABSTRACT: G-quadruplexes are higher-order nucleic acid structures which can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis followed by apoptosis, and down-regulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide (ND) ligands on the basis of cell biological data together with an NCI COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: a) telomere uncapping with subsequent DNA damage response and senescence, b) inhibition of transcription/translation of oncogenes, c) genomic instability though telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis and d) induction of chromosomal instability by telomere aggregate formation.
    Molecular pharmacology 11/2012; 83(2). DOI:10.1124/mol.112.081075 · 4.12 Impact Factor
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    ABSTRACT: 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.
    Organic & Biomolecular Chemistry 04/2012; 10(19):3830-40. DOI:10.1039/c2ob07006e · 3.49 Impact Factor
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