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Selective Delivery of Quinone Methide Precursor QMP by Peptide Nucleic Acids PNAs

The aim of this work is the synthesis of a DNA alkylating linked to a recognition agent. This component helps to prevent undesirable reactions of substrates and direct responsiveness to a specific target. This target is the mRNA of human telomerase.
The mRNA of telomerase was chosen because telomerase activity was detected in many tumor cells, and it would seem a reasonable explanation of their immortalization and their resistance.
The recognition agent used is the PNA (peptidic nucleic acid) or a macromolecule synthetic DNA that mimics the mating of the nucleobases. Other chemical and physical characteristics of the PNA are still very different from those of the DNA molecule, and just for this reason applications are very interesting. The PNA was synthesized using the procedures in the SPPS (Solid Phase Peptide Synthesis).
The alkylating agent is a precursor of quinone methide (QMP) activated by breaking a bond of oxygen - silicon by the fluoride ion. Following this activation, there is the formation of a single molecule in which the quinone methide reacts with the recognition agent, giving birth to the so-called self - adduct, that differently from the free Alkylating has a longer lifetime.
It was also optimized the synthesis of QMP in comparison to the traditional version used by Rokita et al.

Mostra/Nascondi contenuto.
Chapter 1 Introduction 1.1 Importance of DNA Alkylation DNA is one of the most important macromolecules involved in life processes. DNA is composed of four bases, adenine (A), cytosine (C), guanine (G), and thymine (T), which are attached to a 2'-deoxyribose sugar (Figure 1). Sugar molecules are linked together with phosphate groups in the position 3' and 5' generating a strand. This strand can bind to another one in a double helix structure. Figure 1 Bases in the DNA Taking a look at the DNA bases, it is easy to recognize the DNA molecule has different nucleophilic sites. Both nitrogen and oxygen are nucleophile. According to Hard – Soft Acids and Bases teory (HSAB) we can stat the nitrogen sites are softer than the oxygen ones. In general, electrophiles with large dipole moments (hard) react at the oxygens of the bases, while electrophiles with small dipole moments (soft) react at the nitrogen nucleophiles. Of the nitrogen nucleophiles, the N7 of dG is typically regarded as the most nucleophilic site of DNA [1] . 9

Laurea liv.II (specialistica)

Facoltà: Scienze Matematiche, Fisiche e Naturali

Autore: Alessandro Livieri Contatta »

Composta da 71 pagine.

 

Questa tesi ha raggiunto 225 click dal 13/10/2008.

Disponibile in PDF, la consultazione è esclusivamente in formato digitale.