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Pivetta, Claudia (2008) Nuovi agenti antineoplastici basati sull'inibizione selettiva della DNA telomerasi. [Ph.D. thesis]

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Abstract (english)

In the search for new anticancer drugs a major goal is to devise more efficient and selective strategies to reduce typical side effects of traditional chemotherapy.
Telomerase represents an attractive and selective target. It is expressed in 80-90% of tumor cells whereas its expression in non-malignant cells is limited to stem cells and to hematopoietic system cells. Telomerase inhibition should lead to cancer cells death, with minor side effects on somatic cell lines.
Several strategies were developed in order to interfere with telomerase activity and affect cancer cell death pathways. Among potential targets we considered the substrate of the enzyme, telomeric DNA. It consists in a variable number of tandem repeats of G-rich sequences which can fold into G-quadruplex structures.
G-quadruplex formation inhibits telomerase activity by preventing enzyme- DNA recognition. In addition, it forms telomere uncapping cytotoxic processes.
In this work we examined several new compounds as G-quadruplex stabilizers, hence indirect inhibitors of telomerase activity and telomere damage inducers.
Enzyme inhibition and selective interaction with quadruplex vs. double stranded DNA were assessed by biophysical and biochemical techniques such as electromobility shift assay, TRAP assay, UV spectroscopy, fluorescence and circular dichroism.
Cytotoxic effects were evaluated by cell proliferation assays on different tumor cell lines.
Tested compounds belong to three different classes: a library of 2,6 bis-substituted anthraquinones, a series of compounds related to bisantrene and perylene derivatives structurally related to PIPER, a well known G-quadruplex stabilizer.
All compounds were designed to understand SA relationships. In particular the following features were considered:
v extension of the aromatic surface;
v number, nature, length and location of side chains.
For all tested compounds we were able to show a satisfactory correlation between telomerase inhibitory properties and ability to stabilize G-quadruplex structures; the most active binders were also able to induce G-quadruplex from random structures. Finally, data obtained by experiments on cell lines confirmed molecular results.

As far as SA relationships, we highlighted the importance of the extension of the aromatic nucleus and positively charged side chains to obtain a good interaction with G-4 arrangements. We were able to define some structural requirements to improve G-quadruplex stabilization and G-quadruplex-duplex selectivity (based on differences between double stranded and G-quadruplex DNA).
An anthracene nucleus extended by planar groups in the side chains produce similar telomerase inhibitory properties and G-quadruplex stabilization effects if compared to perylene derivatives.
The need for at least two side chains clearly emerged; however an increment in G-quadruplex vs. duplex selectivity could be obtained by incrementing the number of side chains in the aromatic system (based on the different number of grooves in duplex and G-quadruplex DNA structures).
A further point concerns the role of the distance between charged groups in side chains and planar surface of compounds.
Location of side chains substantially affects telomerase inhibitory properties, G-4 stabilization, G-quadruplex-double stranded DNA selectivity and interaction mode with the nucleic acid.
In the study of bisantrene analogues we identified 1,5 positions as the most effective in telomerase inhibition and G-quadruplex stabilization. 2,6 and 2,7 bis- substituted derivatives showed also good anti-telomerase properties but cellular studies suggest a greater cytotoxic effects probably due to a different DNA interaction mode.

SAR data will be used to develop, by rational design, new selective telomerase inhibitors.

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EPrint type:Ph.D. thesis
Tutor:Palumbo, Manlio
Supervisor:Sissi, Claudia
Ph.D. course:Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:31 January 2008
Anno di Pubblicazione:31 January 2008
Key Words:Telomerasi, telomeri, G-quadruplex, quartetti di guanine
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Farmaceutiche
Codice ID:548
Depositato il:08 Sep 2008
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