Diverse iridium peptide bioconjugates and the corresponding iridium/gold bimetallic complexes have been synthesized starting from a cyclometallated carboxylic acid substituted IrIII complex [Ir(ppy)2(Phen‐5‐COO)] by solid phase peptide synthesis (SPPS). The selected peptide sequences were an enkephalin derivative Tyr‐Gly‐Gly‐Phe‐Leu together with the propargyl‐substituted species Tyr‐Gly‐Pgl‐Phe‐Leu to allow gold coordination (Pgl: propyrgyl‐glycine, HC≡C‐Gly), and a specific short peptide, Ala‐Cys‐Ala‐Phen, containing a cysteine residue. Introduction of the gold center has been achieved via a click reaction with the alkynyl group leading to an organometallic Au−C(triazole) species, or by direct coordination to the sulfur atom of the cysteine. The photophysical properties of these species revealed predominantly an emission originating from the Ir complex, using mixed metal‐to‐ligand and ligand‐to‐ligand charge transfer excited states of triplet multiplicity. The formation of the peptide bioconjugates caused a systematic redshift of the emission profiles. Lysosomal accumulation was observed for all the complexes, in contrast to the expected mitochondrial accumulation triggered by the gold complexes. Only the cysteine‐containing Ir/Au bioconjugate displayed cytotoxic activity. The absence of activity may be related to the lack of endosomal/lysosomal escape for the cationic peptide conjugates. Interestingly, the different coordination sphere of the gold atom may play a crucial role, as the Au−S(cysteine) bond may be more readily cleaved in a biological environment than the Au−C(triazole) bond, and thus the Au fragment could be released from or trapped in the lysosomes, respectively. This work represents a starting point in the development of bimetallic peptide bioconjugates as theranostics and in the knowledge of factors that contribute to anti‐proliferative activity.

In the interaction of an [Ir(+i)(COD)(NHC)Cl] complex with model peptides a chelating motif with a particularly interesting bimetallic peptide-bridged Ir(+iii)–NHC motif was identified with loss of the COD and Cl ligands and oxidation of the metal.

While most Rh–N-heterocyclic carbene (NHC) complexes currently investigated in anticancer research contain a Rh­(III) metal center, an increasing amount of research is focusing on the cytotoxic activity and mode of action of square-planar [RhCl­(COD)­(NHC)] (where COD = 1,5-cyclooctadiene) which contains a Rh­(I) center. The enzyme thioredoxin reductase (TrxR) and the protein albumin have been proposed as potential targets, but the molecular processes taking place upon protein interaction remain elusive. Herein, we report the preparation of peptide-conjugated and its nonconjugated parent [RhCl­(COD)­(NHC)] complexes, an in-depth investigation of both their stability in solution, and a crystallographic study of protein interaction. The organorhodium compounds showed a rapid loss of the COD ligand and slow loss of the NHC ligand in aqueous solution. These ligand exchange reactions were reflected in studies on the interaction with hen egg white lysozyme (HEWL) as a model protein in single-crystal X-ray crystallographic investigations. Upon treatment of HEWL with an amino acid functionalized [RhCl­(COD)­(NHC)] complex, two distinct rhodium adducts were found initially after 7 d of incubation at His15 and after 4 weeks also at Lys33. In both cases, the COD and chlorido ligands had been substituted with aqua and/or hydroxido ligands. While the histidine (His) adduct also indicated a loss of the NHC ligand, the lysine (Lys) adduct retained the NHC core derived from the amino acid l-histidine. In either case, an octahedral coordination environment of the metal center indicates oxidation to Rh­(III). This investigation gives the first insight on the interaction of Rh­(I)­(NHC) complexes and proteins at the molecular level.

Complexes of RhI and IrI of the [M(COD)(NHC)X] type (where M=Rh or Ir, COD=1,5‐cyclooctadiene, NHC=N‐heterocyclic carbene, and X=halide) have recently shown promising cytotoxic activities against several cancer cell lines. Initial mechanism of action studies provided some knowledge about their interaction with DNA and proteins. However, information about their cellular localization remains scarce owing to luminescence quenching within this complex type. Herein, the synthesis of two rare examples of luminescent RhI and IrI [M(COD)(NHC)I] complexes with 1,8‐naphthalimide‐based emitting ligands is reported. All new complexes are comprehensively characterized, including with single‐crystal X‐ray structures. Steric crowding in one derivative leads to two distinct rotamers in solution, which apparently can be distinguished both by pronounced NMR shifts and by their respective spectral and temporal emission signatures. When the photophysical properties of these new complexes are exploited for cellular imaging in HT‐29 and PT‐45 cancer cell lines, it is demonstrated that the complexes accumulate predominantly in the endoplasmic reticulum, which is an entirely new finding and provides the first insight into the cellular localization of such IrI(NHC) complexes.

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