: 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
;
Baglini, Emma
Co-primo
Methodology
;
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1170265
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