Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simulta-neous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands sigma R/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K-i sigma R-1 = 38 +/- 3.7; K-i sigma R-2 = 2917 +/- 769 and HDACs IC50 = 0.59 mu M) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 mu M on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over sigma R-1 and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.

Discovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity

di Giacomo, Viviana;Di Rienzo, Annalisa;Cacciatore, Ivana;Cataldi, Amelia;Balaha, Marwa;
2023-01-01

Abstract

Designing and discovering compounds for dual-target inhibitors is challenging to synthesize new, safer, and more efficient drugs than single-target drugs, especially to treat multifactorial diseases such as cancer. The simulta-neous regulation of multiple targets might represent an alternative synthetic approach to optimize patient compliance and tolerance, minimizing the risk of target-based drug resistance due to the modulation of a few targets. To this end, we conceived for the first time the design and synthesis of dual-ligands sigma R/HDACi to evaluate possible employment as innovative candidates to address this complex disease. Among all synthesized compounds screened for several tumoral cell lines, compound 6 (K-i sigma R-1 = 38 +/- 3.7; K-i sigma R-2 = 2917 +/- 769 and HDACs IC50 = 0.59 mu M) is the most promising candidate as an antiproliferative agent with an IC50 of 0.9 mu M on the HCT116 cell line and no significant toxicity to normal cells. Studies of molecular docking, which confirmed the affinity over sigma R-1 and a pan-HDACs inhibitory behavior, support a possible balanced affinity and activity between both targets.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11564/820441
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact