Bioactivity studies of organometallic Cp*Rh(iii) and Au(i) NHC complexes bioconjugated to integrin binding peptides

Integrins are pivotal targets in cancer therapy development due to their overexpression in many tumor cells and neovascular tissue. Arginine-glycine-aspartic acid (RGD) sequence-containing peptides are established ligands for targeting integrins; approximately half of all known integrins recognize this sequence, enabling selective delivery of drugs and imaging agents to tumors and their vasculature. Despite the widespread application of cyclic RGD (cRGD) peptides in oncological research, the number of reported RGD conjugates featuring organometallic payloads remains limited. In this work, we present new Au(i) and Rh(iii) organometallic cRGD conjugates and study their bioactivity by a combination of experimental and theoretical methods. The three organometallic bioconjugates, labelled Rh-RGD, Au-RGD and Au-RGD ₂ , were obtained by integrating Cp*Rh(iii) and Au(i) N-heterocyclic carbene (NHC) complexes into the cyclic peptide c(RGDyK) through chemoselective Rh(iii) coordination at tyrosine and Au(i) NHC wingtip conjugation at the lysine amino group, enabling a direct comparison of distinct organometal-peptide conjugation strategies. Tight-binding density functional theory (DFT) calculations at the αvβ3 Cilengitide pocket indicated that the Rh-RGD complex maintained the peptide recognition mode and dissociation energetics essentially unchanged, whereas Au-RGD engaged weakly with the binding pocket. The in vitro antiproliferative activity studies have shown that RGD conjugation does not necessarily improve the cytotoxicity of the organometallic complexes. However, inductively coupled plasma mass spectrometry (ICP-MS) revealed clear differences in metal uptake, with monomeric Au-RGD efficiently internalized, Rh-RGD closely matching its metal precursor, and Au-RGD ₂ showing negligible accumulation. Altogether, these data pointed to a finely balanced interplay between integrin recognition, steric accessibility, solvation, and metal-centred reactivity, while emphasizing that successful c(RGD)-guided metallopeptides require optimization of organometallic chemistry, and vector design towards the development of the next-generation targeted metallodrugs.