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• W16185841 abstract "The attention around selective recognition of G-Quadruplex has steadily grown during the past 10 years. G-4 are non-canonical DNA structures which can be generated from the self-assembling of guanine rich oligonucleotides. Such an interest is justified by the fact that it is widely recognized that the above structures could act as regulators of biological processes in vivo.In fact, there are several examples of G-Quadruplexes stabilization, by small molecules or engineered antibodies, which is translated into a strong influence of the biological process in which the oligonucleotide is involved. The inhibition of telomerase enzyme as well as the gene transcriptional alteration induced by the stabilization of such structures, represent the most important applications, together with the more recently studied effect on translation mediated by G-4 RNA structures. This makes G-Quadruplex a real therapeutic target useful for the developing of new antitumor drugs. The aim of this work is to develop a new generation of G-4 ligands capable to undergo alkylation triggered by biocompatible protocols. The key aspect of this idea is to regulate the alkylation process, exploiting mild chemical or physical modifications, in order to temporally separate it from the reversible recognition. These molecules would therefore act as molecular devices capable of pre-concentration onto the target and stabilizing the complex through non covalent interactions. These ligands after activation of the masked electrophile are capable to generate the alkylating specie and therefore to achieve a strong covalent interaction.These features would induce an irreversible damage which would not be repaired by the common cellular process, enhancing the effectively drug potency in biological response terms.The basic idea is to exploit molecular recognition properties of already described ligands and tethering to them a masked electrophile. The releasing of the alkylating specie will be achieved exploiting physical or chemical triggers. Such molecules would represent a brand new class of irreversible G-4 ligands which has never been conceived before.The common features that such a class of ligands must have are:1) A wide electron poor and flat surface, which confers molecular recognition properties, exploiting superficial π stacking interactions with the biological target.2) A precursor of an alkylating specie, triggerable by mild physical and chemical activation protocols, possibly exploitable under physiological conditions3) A moiety which can be easily modified through substrate interactions or chemical activation. Such moiety will represent the trigger of the alkylating reactivity.In more details, we had focused our attention on the chemical functionalization of Naphthalimide (NI) and Naphthalendiimide (NDI) derivatives, which both are good G-4 binders according to literature. Quinone Methide precurors (QM) electrophiles have been tethered to the above molecules.QM based alkylating species are particularly suitable for this project because they can be generated from very stable precursors through several biocompatible activation protocols. Moreover, their reactivity could be tuned changing the electronic nature of the phenolic precursor.In this PhD thesis we describe the synthesis, the reactivity and the study concerning the interaction of the synthesized molecules with oligonucleotides capable of G-4 folding.Particular emphasis will be given to the consequences induced by the alkylation damage with potentially achievable application both therapeutic and diagnostic. Moreover, we will discuss a parallel project developed during a period spent in the Cambridge University in Prof. Balasubramanian’s reaserch group." @default.
• W16185841 created "2016-06-24" @default.
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• W16185841 date "2011-01-26" @default.
• W16185841 modified "2023-09-22" @default.
• W16185841 title "New Molecular Devices for Selective Structural Modifications of G-Quadruplex Folded Oligonucleotides" @default.
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