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Sutera Sardo, Manlio (2013) New quinolizinium derivatives: design, synthesis and study on biological and photobiological activity. [Ph.D. thesis]

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Abstract (english)

Neoplastic diseases have become one of the most important causes of death in the world. In USA, cancer is the second cause of death after the cardiovascular diseases. Therefore, the research, the discovery and the development of new compounds with antitumoral activity have become one of the most important goals in medicinal chemistry, also trying to make a selective toxicity towards the diseased or cancer cells, thus not involving the healthy cells. Many therapeutic approaches are available for the treatment of cancer in clinical use: surgery, radiotherapy are used for localized cancer; chemotherapy, hormone-therapy and immunotherapy are considered useful, as systemic treatments, for leukemia and metastatic tumours. In the chemotherapy a high number of molecules interacts with nucleic acids like groove binders, alkylating and intercalator compounds. The molecules that belong to the latter class, interact with DNA by intercalation in the base pairs through van der Waals interactions, hydrogen bonds, hydrophobic and/or charge transfer forces. Therefore, these molecules have attracted, during their development, particular attention as chemotherapeutic agents in medicinal chemistry because the consequences of DNA intercalation by exogenous molecules lead to a significant modification of the DNA structure and may result in a hindered or suppressed function of the nucleic acid in physiological processes. But the clinic application of these compounds has shown some problems such as multidrug resistance (MDR), and secondary and/or collateral effects. These shortcomings have motivated the search of new compounds to be used either in place of, or in conjunction with, the existing molecules.
Condensed poly(hetero)aromatic compounds are usually regarded as representative DNA intercalators, especially if they contain electron-deficient or charged aromatic cores in the structure. Measurement of the binding constant and biological activity of DNA-intercalator complexes and QSAR studies lead to the conclusion that there should exist a relationship between cytotoxic activity and binding force. Otherwise, cytotoxicity is not only dependent on the ability to interact with DNA, since there are many DNA intercalators that are incapable of working as cytotoxic agents: to be effective, a drug must first overcome many barriers, including metabolic pathways, cytoplasmatic and nuclear membranes. Cytotoxicity could be also a consequence of the poisoning of topoisomerases, enzymes that are directly involved in DNA recognition and that regulate DNA topology. They induce cytotoxicity when they act as poisons towards the enzymes by stabilizing the ternary DNA-intercalator-topoisomerase complex in such a way that the enzymatic process cannot continue forward or backward. This complex is detected by the cell as a damaged portion, which triggers a series of events such as cell apoptosis.
Some compounds, called photonucleases, which induce DNA damage after UV-VIS-irradiation, have become interesting; while the association of cationic dyes to DNA is a reversible process, the DNA damage, which frequently occurs on irradiation of ligand-DNA complexes, is often irreversible. The latter DNA damage may lead to cell death or mutation, and must be avoided in healthy systems. However, this photoinduced DNA-damage may be applied in photochemotherapy to remove unwanted cells.
Among the compounds investigated along these lines, the quinolizinium derivatives, such as coralyne and the related molecules, have attracted particular attention. They are arenes containing quaternary bridgehead nitrogen atom and have been shown to bind to DNA and may be employed as a central unit in DNA-targeting drugs. During the studies of the influence of the substituition pattern of quinolizinum derivatives on their intercalation with DNA, it has been shown that the chemical structure of the tetracyclic naphtho[1,2-b]quinolizinium bromide 2 has interesting properties with respect to the binding to nucleic acids. In particular, these intercalators may exhibit a stronger interaction with nucleic acids as compared with the tricyclic benzo[b]quinolizinium 1: the additional benzene moiety extends the surface of the planar chromophore and increases the  stacking between the dye and the DNA bases, resulting in higher binding constants. Other important aspects are represented by the photobiological properties: it was shown that an efficient DNA-strand cleavage is photoinduced by the naphtho[1,2-b]quinolizinium bromide 2.
The compounds synthesized and analyzed in this project were 3-aryl-substituted-naphtho[1,2-b]quinolizinium derivatives; then studies about the DNA-binding properties and cytotoxic activity were carried out. The investigation of these compound allows to evaluate the effects of the extension of  system, by the introduction of fourth aromatic ring, and the effects of the substituent in position 3. This position was chosen for structural analogy with some tricyclic benzo[b]quinolizinium 1, with better biological activity with respect to the not-substituted compound. After these, experiments in comparison to the naphtho[1,2-b]quinolizinum bromide 2, without substituents in position 3, to investigate preliminary molecular target (topoisomerase I and II), to attempt a structure-relactionship-activity and finally photobiological tests will be carried out.

Abstract (italian)

Le neoplasie risultano essere una delle più importanti cause di morte nel mondo: negli Stati Uniti il cancro rappresenta la seconda causa di morte dopo le malattie cardiovascolari. Quindi la ricerca, la scoperta e lo sviluppo di nuovi composti a potenziale attività antitumorale è considerato uno dei più importanti obiettivi in campo della chimica farmaceutica, cercando anche di distinguere in termini di citotossicità le cellule sane da quelle cancerose e malate. Ad oggi, molti approcci terapeutici sono disponibili per il trattamento del cancro in ambito clinico: chirurgia, radioterapia sono usate nel trattamento di tumori localizzati; chemioterapia, terapie ormonali, immunoterapia si sono invece rivelate utili nella cura di leucemia e tumori metastatici. Nell’approccio chemioterapico un alto numero di molecole interagisce con gli acidi nucleici come groove binders, agenti alchilanti e intercalanti. Le molecole che appartengono a quest’ultima classe interagiscono con il DNA intercalandosi appunto fra le coppie di basi attraverso interazioni di Van der Waals, legami idrogeno, legami idrofobici e/o interazioni di carica. Molte di queste molecole hanno suscitato particolare interesse durante il loro sviluppo come potenziali agenti chemioterapici perché è noto che una conseguenza dell’intercalazione da parte di molecole esogene nella doppia elica è proprio una modifica strutturale e chimico-fisica della struttura che vede come risultato un’alterata o arrestata funzione del DNA nei processi fisiologici. Ma l’applicazione clinica di questi composti ha mostrato problemi in termini di insorgenza di resistenze (MDR), effetti secondari o collaterali. Questi inconvenienti hanno spinto alla ricerca di nuovi composti che potessero sostituire o migliorare i composti già esistenti.
I poli(etero)cicli aromatici condensati sono solitamente considerati buoni agenti intercalanti, specialmente se nel core aromatico presentano cariche positive.
Gli studi sulla valutazione quantitativa della costante di binding e sull’attività biologica dei complessi DNA-agenti intercalanti e di QSAR hanno portano alla conclusione che potrebbe esistere una relazione tra attività citotossica e forza di binding. Comunque la citotossicità non è soltanto dipendente dall’abilità a interagire con il DNA, dal momento che alcuni intercalanti si sono rivelati anche non citotossici: infatti per poter esercitare il suo effetto, un farmaco deve prima passare barriere, vie metaboliche, membrane citoplasmatiche e nucleari. La citotossicità può anche essere conseguenza dell’azione di veleno contro le topoisomerasi, enzimi direttamente coinvolti in processi che coinvolgono gli acidi nucleici in fondamentali steps della crescita cellulare e regolano la topologia del DNA. Gli intercalanti del DNA possono esplicare un’azione citotossica attraverso stabilizzazione del complesso DNA-intercalatore-topoisomerasi in modo che il ciclo biochimico venga bloccato. Questo complesso con il DNA danneggiato poi può essere riconosciuto dalla cellula che attiva una serie di vie biochimiche che portano all’apoptosi.
Si sono rivelati anche interessanti quei composti, chiamati fotonucleasi, che inducono danno al DNA dopo irradiazione con luce UV-VIS; mentre l’associazione di cationi organici al DNA è un processo reversibile, il danno al DNA generato dopo irradiazione del complesso ligando-DNA è spesso irreversibile e questo può portare a morte cellulare, mutazioni che dovrebbero essere evitati in sistemi sani. Comunque, un fotodanno al DNA potrebbe essere applicato in fotochemioterapia al fine di rimuovere cellule malate.
Tra i composti studiati in tutto questo contesto, i derivati del chinolizinio, come la coralina e molecole correlate, hanno suscitato particolare interesse. Essi constano di anelli aromatici condensati con una carica positiva sull’azoto quaternario e hanno mostrato di legare il DNA. Durante gli studi sulle modifiche chimiche del chinolizinio in termini di legame al DNA, è stato mostrato che la struttura chimica tetraciclica del nafto[1,2-b]chinolizinio bromuro 2 presenta interessanti proprietà di binding agli acidi nucleici: in particolare viene osservata una forte interazione se comparata al derivato triciclico benzo[b]chinolizinio 1, dovuta all’addizione del quarto anello aromatico che estende la superficie planare del cromoforo ed aumenta le interazioni  tra il composto e le basi del DNA. Altro aspetto importante è rappresentato dalle attività fotobiologiche: è stato mostrato che esiste un efficiente taglio del DNA fotoindotto appunto dal nafto[1,2-b]chinolizinio bromuro 2.
In questo progetto di ricerca sono stati analizzati e sintetizzati derivati 3-aril del nafto[1,2-b]chinolizinio; e successivamente sono stati effettuati studi per determinare la tipologia di binding al DNA e l’attività citotossica. Particolare attenzione è stata riposta sulla valutazione dell’effetto dell’introduzione del quarto anello aromatico e della sostituzione in posizione 3. Quest’ultima posizione è stata scelta in analogia a alcuni derivati del triciclico benzo[b]chinolizinio 1 con migliore attività biologica rispetto alla molecola di partenza. Successivamente prendendo come riferimento il nafto[1,2-b]chinolizinio bromuro 2, senza quindi sostituenti in posizione 3, si sono condotti studi preliminari sull’identificazione, oltre agli acidi nucleici, di un probabile target molecolare (topoisomerasi I e II); si è cercato di ipotizzare una relazione struttura-attività e infine di valutare l’attività fotobiologica.

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EPrint type:Ph.D. thesis
Tutor:Vedaldi, Daniela
Ph.D. course:Ciclo 25 > Scuole 25 > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:25 January 2013
Anno di Pubblicazione:25 January 2013
Key Words:DNA, Topoisomerases, Quinolizinium, Intercalation, Cytotoxicity, Synthesis
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:5490
Depositato il:14 Oct 2013 09:51
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