Preparation of Titanocene–Gold Compounds Based on Highly Active Gold(I)‐N‐Heterocyclic Carbene Anticancer Agents: Preliminary in vitro Studies in Renal and Prostate Cancer Cell Lines. (12th April 2019)

• Record Type: Journal Article
• Authors: Curado, Natalia; Giménez, Nora; Miachin, Kirill; Aliaga‐Lavrijsen, Mélanie; Cornejo, Mike A.; Jarzecki, Andrzej A.; Contel, María
• Is Part Of: ChemMedChem. Volume 14:Number 11(2019)
• Page Start: 1086
• Page End: 1095
• Publication Date: 2019-04-12
• Subjects: Heterometallic compounds -- N-heterocyclic carbenes -- prostate cancer -- renal cancer -- titanocene–gold; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800796
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Heterometallic titanocene‐based compounds containing gold(I)‐phosphane fragments have been extremely successful against renal cancer in vitro and in vivo. The exchange of phosphane by N ‐heterocyclic carbene ligands to improve or modulate their pharmacological profile afforded bimetallic complexes effective against prostate cancer, but less effective against renal cancer in vitro. Herein we report the synthesis of new bimetallic Ti–Au compounds by the incorporation of two previously reported highly active gold(I)‐ N ‐heterocyclic carbene fragments derived from 4, 5‐diarylimidazoles. The two new compounds [(η 5 ‐C5 H5 )2 TiMe(μ‐mba)Au(NHC)] (where NHC=1, 3‐dibenzyl‐4, 5‐diphenylimidazol‐2‐ylidene, NHC‐Bn 2 a ; or 1, 3‐diethyl‐4, 5‐diphenylimidazol‐2‐ylidene, NHC‐Et 2 b ) with the dual linker (‐OC(O)‐ p ‐C6 H4 ‐S‐) containing both a carboxylate and a thiolate group were evaluated in vitro against renal and prostate cancer cell lines. The compounds were found to be more cytotoxic than previously described Ti–Au compounds containing non‐optimized gold(I)‐ N ‐heterocyclic fragments. We present studies to evaluate their effects on cell death pathways, migration, inhibition of thioredoxin reductase (TrxR) and vascular endothelial growth factor (VEGF) in the PC3 prostate cancer cell line. The results show that the incorporation of a second metallic fragment such as titanocene into biologically active gold(I) compounds improves their pharmacological profile. Abstract : Two metals, more power : The incorporation of a titanocene motif into previously described gold(I) compounds containing N ‐heterocyclic carbene ligands improves or does not decrease their cytotoxicity in human renal and prostate PC3 cancer cell lines. Bimetallic compounds display an improved pharmacological profile in terms of apoptosis, inhibition of migration, and inhibition of thioredoxin reductase (TrxR) and vascular endothelial growth factor (VEGF) in prostate cancer cell lines.