: Auranofin ([1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato](triethylphosphine)-gold) is a leading gold-based drug clinically used to treat arthritis. In the last years, it entered various drug reprofiling programs, and it has been found promising against various forms of tumor, including ovarian cancer. Evidence showed as its antiproliferative profile mainly depends on the inhibition of thioredoxin reductase (TrxR), being this mitochondrial system its main target. In this context, we report here the synthesis and biological evaluation of a novel complex designed as auranofin analogue obtained through the conjugation of a phenylindolylglyoxylamide ligand (which belongs to the so-called PIGA TSPO ligand family) with the auranofin-derived cationic fragment [Au(PEt3)]+. This complex is characterized by two parts. The phenylindolylglyoxylamide moiety, owing to its high affinity for TSPO (in the low nM range) should drive the compound to target mitochondria, whereas the [Au(PEt3)]+ cation is the actual anticancer-active molecular fragment. Overall, we wanted to offer the proof-of-concept that by coupling PIGA ligands to anticancer gold active moieties, it is possible to preserve and even improve anticancer effects, opening the avenue to a reliable approach for targeted therapy.

A complex bearing TSPO PIGA ligand coordinated to the [Au(PEt3)]+ pharmacophore is highly cytotoxic against ovarian cancer cells

Chiaverini, Lorenzo
Investigation
;
Poggetti, Valeria
Data Curation
;
Da Settimo, Federico
Writing – Review & Editing
;
Taliani, Sabrina
Validation
;
Barresi, Elisabetta
Writing – Original Draft Preparation
;
La Mendola, Diego
Penultimo
Writing – Review & Editing
;
Marzo, Tiziano
Ultimo
Conceptualization
2023-01-01

Abstract

: Auranofin ([1-(thio-κS)-β-D-glucopyranose-2,3,4,6-tetraacetato](triethylphosphine)-gold) is a leading gold-based drug clinically used to treat arthritis. In the last years, it entered various drug reprofiling programs, and it has been found promising against various forms of tumor, including ovarian cancer. Evidence showed as its antiproliferative profile mainly depends on the inhibition of thioredoxin reductase (TrxR), being this mitochondrial system its main target. In this context, we report here the synthesis and biological evaluation of a novel complex designed as auranofin analogue obtained through the conjugation of a phenylindolylglyoxylamide ligand (which belongs to the so-called PIGA TSPO ligand family) with the auranofin-derived cationic fragment [Au(PEt3)]+. This complex is characterized by two parts. The phenylindolylglyoxylamide moiety, owing to its high affinity for TSPO (in the low nM range) should drive the compound to target mitochondria, whereas the [Au(PEt3)]+ cation is the actual anticancer-active molecular fragment. Overall, we wanted to offer the proof-of-concept that by coupling PIGA ligands to anticancer gold active moieties, it is possible to preserve and even improve anticancer effects, opening the avenue to a reliable approach for targeted therapy.
2023
Chiaverini, Lorenzo; Baglini, Emma; Mannelli, Michele; Poggetti, Valeria; Da Settimo, Federico; Taliani, Sabrina; Gamberi, Tania; Barresi, Elisabetta; La Mendola, Diego; Marzo, Tiziano
File in questo prodotto:
File Dimensione Formato  
A complex bearing TSPO PIGA ligand coordinated to the [Au(PEt3)]+ pharmacophore is highly cytotoxic against ovarian cancer cells.pdf

accesso aperto

Descrizione: A complex bearing TSPO PIGA ligand coordinated to the [Au(PEt3)]+ pharmacophore is highly cytotoxic against ovarian cancer cells
Tipologia: Versione finale editoriale
Licenza: Creative commons
Dimensione 560.79 kB
Formato Adobe PDF
560.79 kB Adobe PDF Visualizza/Apri

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/11568/1170265
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact