Cancer represents a leading cause of death worldwide. The International Agency for Research on Cancer (IARC) declares 19.3 million new cases of cancer in 2020. Despite several therapies are commercially available, new effective treatments are required. A research line of MedChem Lab is focused on the identification of new possible anticancer agents for the treatment of glioblastoma (GB) and multiple myeloma (MM), both diseases characterized by poor survival rates and lack of concrete cure. Recently, the invention of “Substituted vinyl piperazine-piperidine urea compounds” (EP21201359) was approved by the European Patent Office and it could be a valid tool for counteracting these diseases. The first aim of my work was to revise the synthetic protocol applied for the synthesis of these urea derivatives in the perspective of Green Chemistry. Where it was possible, conventional heating was replaced by microwave heating and microencapsulated catalyst was used to reduce heavy metal contamination and reuse it. The key intermediate was synthetized applying a one-pot procedure. Lastly, for the purification crystallization and “catch and release” methodology employing resins allowed an easy and rapid recovery of the product. Combined together, all these strategies permitted to enhance yields and minimized the use of toxic reagents and high amounts of waste. Not less important, costs and time of reaction routes were drastically reduced. Lastly, to improve our knowledge regarding anticancer activity compounds: an available synthetic strategy for the preparation of homologous derivatives was set- up.
Il cancro rappresenta una delle maggiori cause di morte nel mondo: nel 2020, secondo l’International Agency for Research on Cancer (IARC), sono stati diagnosticati circa 19.3 milioni di nuovi casi. Nonostante molte terapie siano ad oggi disponibili commercialmente, vi è l’esigenza di introdurre nuovi farmaci efficaci. Una linea di ricerca del MedChem Lab è focalizzata sull’identificazione di nuovi possibili agenti anticancro per il trattamento del glioblastoma (GB) e del mieloma multiplo (MM): entrambe le patologie sono caratterizzate da una prognosi infausta e dalla mancanza di una cura concreta. Recentemente è stato approvato dall’European Patent Office il brevetto “Substituted vinyl piperazine-piperidine urea compounds” (EP21201359), il quale potrebbe essere un valido strumento per contrastare queste patologie. Il primo obiettivo del mio lavoro di tesi è stato quello di revisionare la procedura sintetica per l’ottenimento di questi derivati ureidici e di modificarla in un'ottica ecosostenibile. Il riscaldamento convenzionale è stato sostituito dal riscaldamento tramite microonde, laddove possibile, e l’utilizzo di catalizzatori microincapsulati ha permesso di ridurre la contaminazione da metalli pesanti. L’intermedio chiave è stato sintetizzato tramite una procedura sintetica one-pot. Infine, metodi di purificazione quali cristallizzazione e l’utilizzo di resine “catch and release” sono stati utilizzati per un facile e rapido recupero del prodotto. Queste strategie introdotte hanno permesso di migliorare le rese di reazione e minimizzare l’uso di reagenti tossici e la quantità di scarto. Non meno importante, i costi e i tempi della via di sintesi sono stati ridotti drasticamente. Infine, è stata sviluppata una strategia sintetica per la preparazione di omologhi dei derivati ureidici, con lo scopo di ampliare la nostra conoscenza riguardo la loro attività anticancro.
Substituted allyl piperazine derivatives as novel anticancer agents: set up of a green synthetic strategy
PIAGGI, FEDERICA
2021/2022
Abstract
Cancer represents a leading cause of death worldwide. The International Agency for Research on Cancer (IARC) declares 19.3 million new cases of cancer in 2020. Despite several therapies are commercially available, new effective treatments are required. A research line of MedChem Lab is focused on the identification of new possible anticancer agents for the treatment of glioblastoma (GB) and multiple myeloma (MM), both diseases characterized by poor survival rates and lack of concrete cure. Recently, the invention of “Substituted vinyl piperazine-piperidine urea compounds” (EP21201359) was approved by the European Patent Office and it could be a valid tool for counteracting these diseases. The first aim of my work was to revise the synthetic protocol applied for the synthesis of these urea derivatives in the perspective of Green Chemistry. Where it was possible, conventional heating was replaced by microwave heating and microencapsulated catalyst was used to reduce heavy metal contamination and reuse it. The key intermediate was synthetized applying a one-pot procedure. Lastly, for the purification crystallization and “catch and release” methodology employing resins allowed an easy and rapid recovery of the product. Combined together, all these strategies permitted to enhance yields and minimized the use of toxic reagents and high amounts of waste. Not less important, costs and time of reaction routes were drastically reduced. Lastly, to improve our knowledge regarding anticancer activity compounds: an available synthetic strategy for the preparation of homologous derivatives was set- up.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/14572