The aim of this PhD project is to synthesize new tubulin-inhibitors. These small molecules are able to bind tubulin at the colchicine-binding site and so their antitumor activity is linked to the interfering with mitotic spindle formation. Because of this, they are able to induce cell death. Furthermore, they act as vascular disrupting agents (VDAs). The general structure of these new molecules comes from the rigidification of combretastatin A-4 (CA-4), that is the natural compound taken as referee. Its structure is reported in the picture below and its phosphate salt pro-drug has recently been approved in some solid cancer treatment. CA-4 is a very promising compound, but the cis-double bond (fundamental for the correct substituents’ orientation) in vivo is transformed in the inactive trans-isomer. To rigidify the molecule, the double bond is replaced by different heterocycles. In this project, the evaluated heterocycles are: • Pyrazoles: the tri-methoxyphenyl ring A has been maintained both in position 3’ and 4’, while the different substituted ring B has been introduced in 4’ and 3’ position; • Pyrroles: the tri-methoxyphenyl ring A has been maintained, while ring B bears different substituents. For some compounds, the pyrrol nitrogen has been alkylated with short alkylic chains; • 1,2,4-triazole-3,5-diamines: the tri-methoxyphenyl ring A has been placed to a bigger distance from ring B; • 1,2,4]triazolo [1,5-a]pyrimidine- 2,7-diamines: it is a further rigidification of the previous ring. Ring B rotation is limited and this ring lay on the same floor of the tri-methoxyphenyl ring A. The last part of project took into consideration hybrid compounds: the aim was to get molecules with dual activity. These had to act both as tubulin polymerization inhibitors and as histone deacetylase inhibitors. Indeed, HDAC is an overexpressed enzyme in some tumors and is one of the main responsible of tumor chemoresitance. The tri-methoxyphenyl ring A was maintained in the design of these molecules, while the importance of the methoxy group in ring B was evaluated: different analogues with 0-3 methoxy groups were synthesized; the core of these compounds was the 6-methoxy-3-methyl-benzofurane, linked with a short spacer to the hydroxamic group (that is the Zinc Binding Domain present in each HDAC inhibitor).
In questo progetto di Dottorato Industriale sono stati sintetizzati nuovi inibitori della tubulina: queste molecole si legano al sito di legame della colchicina e, cosi' facendo, esercitano la loro attivita' antitumorale interferendo con la formazione del fuso mitotico (pertanto inducendo morte cellulare) ed agiscono anche come VDA (Vascular Disrupting Agents). Per la progettazione delle nuove strutture ci si e’ basati sulla rigidificazione di combretastatina A-4 (CA-4), molecola di riferimento di origine naturale riportata nella figura sottostante, il cui profarmaco sale di fosfato e' recentemente stato approvato per il trattamento di alcuni tumori solidi. Questa molecola e’ molto promettente, pero’ in vivo il doppio legame cis -indispensabile per la corretta orientazione dei sostituenti- isomerizza all’inattivo trans. La rigidificazione viene indotta mediante sostituzione del doppio legame olefinico con opportuni eterocicli. Quelli considerati in questo progetto sono: • Pirazoli: l’anello A trimetossifenile e’ stato introdotto sia in posizione 3’ che 4’ del pirazolo (analogamente, l’anello B diversamente sostituito e’ stato introdotto in posizione 4’ e 3’); • Pirroli: l’anello A trimetossifenile viene mantenuto, mentre l’anello B presenta diversi sostituienti. Per alcuni composti, l’azoto del pirazolo e’ stato alchilato con brevi catene alchiliche; • 1,2,4-triazoli-3,5-diammine: l’anello A trimetossifenile presenta un distanziamento maggiore dall’anello B; • [1,2,4]triazolo-[1,5-a]pirimidina-2,7-diammine: pensato come ulteriore rigidificazione del precedente anello. Si va a limitare la rotazione dell’anello B, mantenendolo sullo stesso piano dell’anello A trimetossifenile; Nell’ultima fase del progetto, e’ stata presa in considerazione la progettazione di composti ibridi con attivita’ duale, ovvero composti in grado di agire sia come inibitori della polimerizzazione della tubulina, sia come inibitori di istone deacetilasi (HDAC, enzima spesso overespresso in alcune forme tumorali, responsabile della mancata capacita’ della cellula tumorale di rispondere a segnali apoptotici e/o ad altri agenti chemioterapici). Nel disegnare queste molecole, e’ stato mantenuto l’anello A trimetossifenile: qui si e’ voluta analizzare l’importanza dei metossi per l’attivita’ di inibizione della proliferazione cellulare, pertanto sono stati sintetizzati analoghi con 0-3 gruppi OMe. Il core di queste molecole e’ costutituito da 6-metossi-3-metil-benzofurano, collegato mediante uno spacer molto corto al gruppo idrossammico, ovvero lo Zinc Binding Domain caratteristico degli inibitori HDAC.
Synthesis of small molecules with antitumoral activity that are able to interfere with the mitotic spindle formation
-
2022
Abstract
The aim of this PhD project is to synthesize new tubulin-inhibitors. These small molecules are able to bind tubulin at the colchicine-binding site and so their antitumor activity is linked to the interfering with mitotic spindle formation. Because of this, they are able to induce cell death. Furthermore, they act as vascular disrupting agents (VDAs). The general structure of these new molecules comes from the rigidification of combretastatin A-4 (CA-4), that is the natural compound taken as referee. Its structure is reported in the picture below and its phosphate salt pro-drug has recently been approved in some solid cancer treatment. CA-4 is a very promising compound, but the cis-double bond (fundamental for the correct substituents’ orientation) in vivo is transformed in the inactive trans-isomer. To rigidify the molecule, the double bond is replaced by different heterocycles. In this project, the evaluated heterocycles are: • Pyrazoles: the tri-methoxyphenyl ring A has been maintained both in position 3’ and 4’, while the different substituted ring B has been introduced in 4’ and 3’ position; • Pyrroles: the tri-methoxyphenyl ring A has been maintained, while ring B bears different substituents. For some compounds, the pyrrol nitrogen has been alkylated with short alkylic chains; • 1,2,4-triazole-3,5-diamines: the tri-methoxyphenyl ring A has been placed to a bigger distance from ring B; • 1,2,4]triazolo [1,5-a]pyrimidine- 2,7-diamines: it is a further rigidification of the previous ring. Ring B rotation is limited and this ring lay on the same floor of the tri-methoxyphenyl ring A. The last part of project took into consideration hybrid compounds: the aim was to get molecules with dual activity. These had to act both as tubulin polymerization inhibitors and as histone deacetylase inhibitors. Indeed, HDAC is an overexpressed enzyme in some tumors and is one of the main responsible of tumor chemoresitance. The tri-methoxyphenyl ring A was maintained in the design of these molecules, while the importance of the methoxy group in ring B was evaluated: different analogues with 0-3 methoxy groups were synthesized; the core of these compounds was the 6-methoxy-3-methyl-benzofurane, linked with a short spacer to the hydroxamic group (that is the Zinc Binding Domain present in each HDAC inhibitor).| File | Dimensione | Formato | |
|---|---|---|---|
|
tesi_Padroni.pdf
Open Access dal 11/06/2023
Descrizione: tesi_Padroni
Tipologia:
Tesi di dottorato
Dimensione
2.82 MB
Formato
Adobe PDF
|
2.82 MB | Adobe PDF | Visualizza/Apri |
I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
