Alkynyl gold(I) phosphane complexes: Evaluation of structure–activity-relationships for the phosphane ligands, effects on key signaling proteins and preliminary in-vivo studies with a nanoformulated complex

Abstract

Gold alkynyl complexes with phosphane ligands of the type (alkynyl)Au(I)(phosphane) represent a group of bioorganometallics, which has only recently been evaluated biologically in more detail. Structure-activity-relationship studies regarding the residues of the phosphane ligand (P(Ph)3, P(2-furyl)3, P(DAPTA)3, P(PTA)3, P(Et)3, P(Me)3) of complexes with an 4-ethynylanisole alkyne ligand revealed no strong differences concerning cytotoxicity. However, a relevant preference for the heteroatom free alkyl/aryl residues concerning inhibition of the target enzyme thioredoxin reductase was evident. Complex 1 with the triphenylphosphane ligand was selected for further studies, in which clear effects on cell morphology were monitored by time-lapse microscopy. Effects on cellular signaling were determined by ELISA microarrays and showed a significant induction of the phosphorylation of ERK1 (extracellular signal related kinase 1), ERK2 and HSP27 (heat shock protein 27) in HT-29 cells. Application of 1 in-vivo in a mouse xenograft model was found to be challenging due to the low solubility of the complex and required a formulation strategy based on a peanut oil nanoemulsion.

The anticancer effect related to disturbances in redox balance on Caco-2 cells caused by an alkynyl gold(I) complex

“…On the other hand, GSR lack of this a selenylsulfide/selenothiol motif and in consequence the access of drugs in general, and [Au(C CPh)(PTA)] in particular, to the active centre might be hamper, impeding drug inhibition. The inhibition of TrxR activity has been also found in different alkynyl gold(I) derivatives reported previously [89][90][91][92][93]. These results suggest a selectivity of gold alkynyl compounds towards TrxR over other related enzymes such as GSR, as it was previously described in the literature by Meyer et al [93].…”

Anticancer Gold N‐Heterocyclic Carbene Complexes: A Comparative in vitro and ex vivo Study

“…It should be noted that, recently,A u I complexes of the type (alkynyl)Au I (phosphane), containing an anionic alkynyl group as well as an eutralp hosphane ligand, have been shown to possess interesting anticancer effects in vitro and in vivo. [35,36] However,t ot he best of our knowledge the anticancer properties of mixed NHC-alkynyl Au I complexes have not been reported so far.F inally,f or comparison purposes and to evaluate the effect of the metal ion on the biological activity,t he Pt II (5) analogueo f2 was also synthesized.…”

Gold and platinum alkynyl complexes for biomedical applications

“…These compounds have displayed significant anti-angiogenic effects in zebrafish embryos in addition to a decrease of tumor cell impedance and extracellular acidification, which points to mitochondria as a major target organelle, similarly to other gold metallodrugs. [36][37][38][39][40][41] Complex 6 was selected for further studies 42 that included tumor selectivity and mechanistic approaches related to protein kinases. Thus, microscopic live cell imaging revealed morphological changes in RC124 kidney cells during the first 6 h of exposure to complex 6 consistent with the presence of interactions of the gold compound with components of the cell surface or extracellular matrix.…”