Antibody-Drug Conjugates (ADCs) are emerging as the next generation anticancer therapeutic agents. ADCs take advantage of the specificity of monoclonal antibody to target the delivery of drugs to the tumor site, with an expectation of improving the efficacy and safety of the cytotoxic payload. The linker plays a key role in the development of ADC derivatives and its blood stability as well as its possible degradation into the cell need to be carefully tuned. The synthesis of the linker offers many opportunities for organic chemistry. In this thesis we explored several different aspects of the ADC field. We developed the first ADC charged with a hydroxamic acid payload (the HDAC inhibitor vorinostat), connected through a metabolic sensitive linker. Moreover, the presence of a not highly cytotoxic drug leads to a lower systemic toxicity compared the one generally observed with traditional ADCs. With regard to self-immolative spacers, we designed a novel multifunctional branched linker that offers the opportunity of a modular synthesis of the various ADCs components. This linker is able to release a model of an amine payload from a disulfide trigger moiety. Furthermore, we present also studies towards a convergent approach to the synthesis of the linker. Besides the work on bioconjugates, we report the preparation of several synthetic impurities of the melatonin receptors agonist Tasimelteon and a new protecting group-free stereoselective synthesis of the sphingosine-1-phosphate receptor agonist Ozanimod.

Gli Antibody-Drug Conjugates (ADC) sono tra i farmaci più promettenti per la terapia mirata antitumorale. Gli ADC sfruttano infatti la capacità degli anticorpi monoclonali di indirizzare il trasporto di molecole citotossiche in modo selettivo al sito del tumore, con un miglioramento dell’efficacia della sicurezza del farmaco citotossico. La porzione linker di collegamento tra l’anticorpo e il farmaco è una componente cruciale di ogni ADC: deve essere stabile in plasma ma instabile all’interno della cellula, permettendo il rilascio del farmaco citotossico solo nell’ambiente citoplasmatico ed evitando un rilascio prematuro nella circolazione sanguigna. In questo progetto di tesi sono stati esplorati numerosi aspetti degli ADC. Abbiamo sviluppato il primo ADC coniugato con un acido idrossamico, l’inibitore dell’enzima istone deacetilasi vorinostat, connesso attraverso un linker degradabile dal metabolismo cellulare. Inoltre, il farmaco è meno potente di quelli solitamente usati negli ADC con una ridotta tossicità sistemica. Per quanto riguarda i “self-immolative spacers”, abbiamo sviluppato un nuovo linker ramificato che permette la possibilità di una sintesi modulare dei vari componenti: tale linker è capace di rilasciare un modello di farmaco citotossico mediante la riduzione di un gruppo disolfuro. Inoltre, sono stati effettuati anche studi verso un approccio convergente alla sintesi dei linker. Oltre al lavoro con i bioconiugati, sono stati sintetizzate alcune impurezze della sintesi industriale dell’agonista dei recettori della melatonina Tasimelteon ed è stata sviluppata una nuova sintesi stereoselettiva dell’agonista dei recettori della sfingosina Ozanimod.

Cianferotti, C. (2019). Synthetic approaches to novel linkers for the bioconjugation of pharmaceutical active compounds.

Synthetic approaches to novel linkers for the bioconjugation of pharmaceutical active compounds

CIANFEROTTI, CLAUDIO
2019-01-01

Abstract

Antibody-Drug Conjugates (ADCs) are emerging as the next generation anticancer therapeutic agents. ADCs take advantage of the specificity of monoclonal antibody to target the delivery of drugs to the tumor site, with an expectation of improving the efficacy and safety of the cytotoxic payload. The linker plays a key role in the development of ADC derivatives and its blood stability as well as its possible degradation into the cell need to be carefully tuned. The synthesis of the linker offers many opportunities for organic chemistry. In this thesis we explored several different aspects of the ADC field. We developed the first ADC charged with a hydroxamic acid payload (the HDAC inhibitor vorinostat), connected through a metabolic sensitive linker. Moreover, the presence of a not highly cytotoxic drug leads to a lower systemic toxicity compared the one generally observed with traditional ADCs. With regard to self-immolative spacers, we designed a novel multifunctional branched linker that offers the opportunity of a modular synthesis of the various ADCs components. This linker is able to release a model of an amine payload from a disulfide trigger moiety. Furthermore, we present also studies towards a convergent approach to the synthesis of the linker. Besides the work on bioconjugates, we report the preparation of several synthetic impurities of the melatonin receptors agonist Tasimelteon and a new protecting group-free stereoselective synthesis of the sphingosine-1-phosphate receptor agonist Ozanimod.
2019
Cianferotti, C. (2019). Synthetic approaches to novel linkers for the bioconjugation of pharmaceutical active compounds.
Cianferotti, Claudio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1071010
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