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

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 [(η5 -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.This work was supported by the US National Cancer Institute and the US National Institute for General Medical Sciences (NIGMS) grants 1SC1CA182844 and 2SC1GM127278‐05A1 (to M.C.). N.C. acknowledges a postdoctoral fellowship from the Fundación Alfonso Martín Escudero (Spain). N.G. thanks the Universidad de la Rioja (Spain) for a doctoral fellowship and a travel scholarship. M.A. thanks the Ministerio de Economía y Ciencia (MINECO, Spain) for a doctoral fellowship and a travel scholarship.Peer reviewe