Synthesis of chalcones derivatives as inhibitors of Notch signaling in T-cell acute lymphoblastic leukemia The Notch signaling pathway is an inter-cellular communication system driving many biological processes in different tissues and in a wide spectrum of organisms. For this reason is considered a rationale target in the therapy of cancers those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL) [1]. Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side effects. By functional and biological analyses of the most representative molecules of an in-house library of natural products, butein (2′,3,4,4′-tetrahydroxychalcone) was identified as valuable lead compound, thus emphasizing the relevance of the chalcone scaffold in Notch inhibition. The combination of drug design, synthesis and biological assays enabled the lead optimization in terms of potency, therapeutic index and phisico-chemical. Notably, the strategy employed to synthesize chalcones in excellent yield was based on the Claisen-Schmidt condensation: twenty-six chemical derivatives were synthesized and tested in vitro [2]. Structure-activity relationships (SAR) were afforded, and a novel potent Notch inhibitor, namely 8, was identified [3] (Fig.1). Short term treatments with compound 8 resulted in a dose-dependent manner decrease of Notch signalling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. In conclusion, our data indicate that 8 is a novel Notch inhibitor, candidate for further investigation and development as therapeutic choice against Notch-dependent cancers. References: [1]. Weng AP et al., (2004). Science; 269-271. [2]. Sogawa Set al., (1994). Biol Pharm Bull.; 251-256. [3]. Mori M. et al., (2017). Scientific Reports; 7:2213.

Synthesis of Chalcone Derivatives As Inhibitors Of Notch Signaling In T-cell Acute Lymphoblastic Leukemia / Romeo, Isabella; Tottone, Luca; Palermo, Rocco; Mori, Mattia; Screpanti, Isabella; Botta, Bruno; Quaglio, Deborah; Ingallina, Cinzia. - (2018). ((Intervento presentato al convegno COST ACTION CM1407: 3rd Training School: Computational modeling tools in drug discovery with natural products tenutosi a Universidad La Laguna, Tenerife (Spain).

Synthesis of Chalcone Derivatives As Inhibitors Of Notch Signaling In T-cell Acute Lymphoblastic Leukemia

Isabella Romeo
;
Luca Tottone;Rocco Palermo;Mattia Mori;Isabella Screpanti;Bruno Botta;Deborah Quaglio;Cinzia Ingallina
2018

Abstract

Synthesis of chalcones derivatives as inhibitors of Notch signaling in T-cell acute lymphoblastic leukemia The Notch signaling pathway is an inter-cellular communication system driving many biological processes in different tissues and in a wide spectrum of organisms. For this reason is considered a rationale target in the therapy of cancers those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL) [1]. Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side effects. By functional and biological analyses of the most representative molecules of an in-house library of natural products, butein (2′,3,4,4′-tetrahydroxychalcone) was identified as valuable lead compound, thus emphasizing the relevance of the chalcone scaffold in Notch inhibition. The combination of drug design, synthesis and biological assays enabled the lead optimization in terms of potency, therapeutic index and phisico-chemical. Notably, the strategy employed to synthesize chalcones in excellent yield was based on the Claisen-Schmidt condensation: twenty-six chemical derivatives were synthesized and tested in vitro [2]. Structure-activity relationships (SAR) were afforded, and a novel potent Notch inhibitor, namely 8, was identified [3] (Fig.1). Short term treatments with compound 8 resulted in a dose-dependent manner decrease of Notch signalling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. In conclusion, our data indicate that 8 is a novel Notch inhibitor, candidate for further investigation and development as therapeutic choice against Notch-dependent cancers. References: [1]. Weng AP et al., (2004). Science; 269-271. [2]. Sogawa Set al., (1994). Biol Pharm Bull.; 251-256. [3]. Mori M. et al., (2017). Scientific Reports; 7:2213.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/1559745
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