Claudia Pivetta

University of Padova, Padua, Veneto, Italy

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Publications (4)15.53 Total impact

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    ABSTRACT: Three novel 2,7-substituted acridine derivatives were designed and synthesized to investigate the effect of this functionalization on their interaction with double-stranded and G-quadruplex DNA. Detailed investigations of their ability to bind both forms of DNA were carried out by using spectrophotometric, electrophoretic, and computational approaches. The ligands in this study are characterized by an open-chain (L1) or a macrocyclic (L2, L3) framework. The aliphatic amine groups in the macrocycles are joined by ethylene (L2) or propylene chains (L3). L1 behaved similarly to the lead compound m-AMSA, efficiently intercalating into dsDNA, but stabilizing G-quadruplex structures poorly, probably due to the modest stabilization effect exerted by its protonated polyamine chains. L2 and L3, containing small polyamine macrocyclic frameworks, are known to adopt a rather bent and rigid conformation; thus they are generally expected to be sterically impeded from recognizing dsDNA according to an intercalative binding mode. This was confirmed to be true for L3. Nevertheless, we show that L2 can give rise to efficient π-π and H-bonding interactions with dsDNA. Additionally, stacking interactions allowed L2 to stabilize the G-quadruplex structure: using the human telomeric sequence, we observed the preferential induction of tetrameric G-quadruplex forms. Thus, the presence of short ethylene spacers seems to be essential for obtaining a correct match between the binding sites of L2 and the nucleobases on both DNA forms investigated. Furthermore, current modeling methodologies, including docking and MD simulations and free energy calculations, provide structural evidence of an interaction mode for L2 that is different from that of L3; this could explain the unusual stabilizing ability of the ligands (L2>L3>L1) toward G-quadruplex that was observed in this study.
    ChemMedChem 10/2010; 5(12):1995-2005. · 2.84 Impact Factor
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    ABSTRACT: The use of small molecules able to induce and stabilize selected G-quadruplex arrangements can cause telomerase inhibition and telomere dysfunction in cancer cells, thus providing very selective therapeutic approaches. Effective stabilizers usually comprise a planar aromatic portion to grant effective stacking onto the G-quartet and positively charged side chains to exploit the highly negative charge density on the quadruplex grooves. Since the relative position of these two pharmacophoric moieties is expected to play an important role in DNA folding stabilization, we evaluated a series of anthracene derivatives substituted with one or two 4,5-dihydro-1H-imidazol-2-yl-hydrazonic groups (the bisantrene side chain) at different positions of the aromatic system. Indeed, the various regioisomers showed distinct binding affinities for telomeric G-quadruplex, and the most effective was the 1,5 and 1,7 bis-substituted analogues. On turn, the 1,8 regioisomer was poorly effective. Interestingly, G-quadruplex binding is clearly related to telomerase inhibition in this class of compounds, thus confirming their ability to shift the nucleic acid conformational equilibrium upon binding and consequently produce interference with the telomere processing enzyme. Additionally, the 1,5 regioisomer was shown to inhibit telomerase activity at lower concentrations than those required to reduce tumor cell proliferation. Comparative analysis of drug effects in telomerase-positive and telomerase-negative cancer cells showed consistent cell growth impairment, as a consequence of activation of the senescence pathway, which was mainly attributable to anthracene-mediated telomere dysfunction.
    Biochemical pharmacology 03/2010; 79(12):1781-90. · 4.25 Impact Factor
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    ABSTRACT: The telomerase-telomere complex is a prospective anticancer target. To inhibit enzyme activity by induction of G-quadruplex in human telomeres, we have synthesized a small library of 2,6- and 2,7-amino-acyl/ peptidyl anthraquinones with diverse connecting linkers, charge, lipophilicity and bulk. The test compounds modulated G-quadruplex stability to different extents and showed clear preference for quadruplex over duplex DNA. Telomerase inhibition correlated with G-quadruplex stabilization. A SAR analysis showed that type of linkage between the linker and the anthraquinone, together with the position of the side chains and the nature of the amino acid components play a major role both in stabilizing G-quadruplex and producing telomerase inhibition. Short-term cytotoxic activity was poor. However, after prolonged exposure to effective G-quadruplex binders, cells became senescent. These results are of help in the rational design of more efficient G-quadruplex stabilizers, possibly endowed with cancer cell-selective antiproliferative effects.
    Journal of Medicinal Chemistry 09/2008; 51(18):5566-74. · 5.61 Impact Factor
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    ABSTRACT: The stabilisation of different G-quadruplex intra- and intermolecular structures by a number of perylene derivatives characterised by side chains ending with linear or cyclic amines was investigated by electrophoretic (EMSA) and spectroscopic (CD) techniques. The G-rich sequences included the biologically relevant human telomeric TTAGGG runs and the NHE region of the c-myc oncogene. The test compounds could be subdivided into two families: derivatives carrying a cyclic amine in the side chains, which show a reduced binding to the G-quadruplex form, and linear amine congeners, exhibiting enhanced affinity. The latter efficiently induce pairing of multiple DNA chains, while the former are not able to overcome the original folding of the nucleic acid sequence which is preserved in the complex. Remarkably, addition of the perylenes to G-rich sequences paired in a double helical form results in G-quadruplex induction by weak binders only. This is likely related to the ability of strong G-quadruplex binders, but not of weak G-quadruplex binders, to efficiently intercalate into the double-stranded arrangement, which becomes stabilised and is not prone to undergo denaturation and subsequent G-quadruplex folding essentially for kinetic reasons. Hence, two apparently conflicting requirements emerge from this work. In fact, linear alkylamino terminals in the perylene side chains are capable of strong and selective G-quadruplex recognition, but only cyclic amine end groups favour duplex-quadruplex transitions that are likely crucial to produce biological and pharmacological effects in living systems.
    Bioorganic & medicinal chemistry 09/2008; 16(20):9331-9. · 2.82 Impact Factor