Journal
CHEMMEDCHEM
Volume 14, Issue 11, Pages 1086-1095Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201800796
Keywords
Heterometallic compounds; N-heterocyclic carbenes; prostate cancer; renal cancer; titanocene-gold
Categories
Funding
- US National Cancer Institute
- US National Institute for General Medical Sciences (NIGMS) [1SC1CA182844, 2SC1GM127278-05A1]
- Fundacion Alfonso Martin Escudero (Spain)
- Universidad de la Rioja (Spain)
- Ministerio de Economia y Ciencia (MINECO, Spain)
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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 [(eta(5)-C5H5)(2)TiMe(mu-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-C6H4-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.
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