Considering the great interest in the field of peptidomimetics and the potentiality of the norbornene scaffold, this thesis has been primarily devoted to the synthesis and exploitation a of new class of β-substituted norbornene amino acids as cysteine mimics. The project has been developed with the aim to fill the gap unexpectedly present in the literature in this field and to confirm the unexploited properties of norbornene amino acid as potential building block for peptidomimetics synthesis. At first, we followed the purpose to individuate a novel synthetic strategy to obtain, not only simple but also highly functionalized, norbornene scaffold in grams scale synthesis, in order to make possible further developments in this field and interesting practical applications. Subsequently, we set out to design, realize and conformationally analyze model peptides containing norbornene amino acids in order to demonstrate the ability of such compounds to behave as strong inducers of helical structure and the possibility to be used in the synthesis of unnatural peptides of therapeutic interest. Finally, we explored the field of small molecules as peptidomimetics and demonstrated the advantage of rigid core in the development of new drugs. To do this, we planned to design and realise new chemical entities based on an extensively modified norbornene scaffold which have shown high activity in modulation of Rac1-Tiam1 protein-protein interactions resulting in a new class of potent inhibitors.. During the synthesis of such molecules we also launched a study aiming to better understand which kind of effects a constrained chemical structure, as norbornene scaffold, could have on the regiochemistry in palladium chemistry, imposing a methodic analysis of the steric and electronic effects in the reaction mechanisms.

SYNTHESIS OF NEW CONFORMATIONALLY CONSTRAINED BETA-SULFANYL-ALFA- AMINO ACIDS AND THEIR EXPLOITATION IN THE SYNTHESIS OF PEPTIDOMIMETICS / A. Ruffoni ; supervisor: F. Clerici ; coordinator: E. Valoti. - : . DIPARTIMENTO DI SCIENZE FARMACEUTICHE, 2014 Feb 25. ((26. ciclo, Anno Accademico 2013. [10.13130/ruffoni-alessandro_phd2014-02-25].

SYNTHESIS OF NEW CONFORMATIONALLY CONSTRAINED BETA-SULFANYL-ALFA- AMINO ACIDS AND THEIR EXPLOITATION IN THE SYNTHESIS OF PEPTIDOMIMETICS

A. Ruffoni
2014-02-25

Abstract

Considering the great interest in the field of peptidomimetics and the potentiality of the norbornene scaffold, this thesis has been primarily devoted to the synthesis and exploitation a of new class of β-substituted norbornene amino acids as cysteine mimics. The project has been developed with the aim to fill the gap unexpectedly present in the literature in this field and to confirm the unexploited properties of norbornene amino acid as potential building block for peptidomimetics synthesis. At first, we followed the purpose to individuate a novel synthetic strategy to obtain, not only simple but also highly functionalized, norbornene scaffold in grams scale synthesis, in order to make possible further developments in this field and interesting practical applications. Subsequently, we set out to design, realize and conformationally analyze model peptides containing norbornene amino acids in order to demonstrate the ability of such compounds to behave as strong inducers of helical structure and the possibility to be used in the synthesis of unnatural peptides of therapeutic interest. Finally, we explored the field of small molecules as peptidomimetics and demonstrated the advantage of rigid core in the development of new drugs. To do this, we planned to design and realise new chemical entities based on an extensively modified norbornene scaffold which have shown high activity in modulation of Rac1-Tiam1 protein-protein interactions resulting in a new class of potent inhibitors.. During the synthesis of such molecules we also launched a study aiming to better understand which kind of effects a constrained chemical structure, as norbornene scaffold, could have on the regiochemistry in palladium chemistry, imposing a methodic analysis of the steric and electronic effects in the reaction mechanisms.
CLERICI, FRANCESCA
VALOTI, ERMANNO
amino acid ; cyclic aminoacid ; norbornene ; palladium ; Heck ; peptidomimetic ; Rac 1 ; umpolung ; helical peptide ; medicinal chemistry ; organic chemistry ; molecular modeling
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore CHIM/05 - Scienza e Tecnologia dei Materiali Polimerici
SYNTHESIS OF NEW CONFORMATIONALLY CONSTRAINED BETA-SULFANYL-ALFA- AMINO ACIDS AND THEIR EXPLOITATION IN THE SYNTHESIS OF PEPTIDOMIMETICS / A. Ruffoni ; supervisor: F. Clerici ; coordinator: E. Valoti. - : . DIPARTIMENTO DI SCIENZE FARMACEUTICHE, 2014 Feb 25. ((26. ciclo, Anno Accademico 2013. [10.13130/ruffoni-alessandro_phd2014-02-25].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/232418
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