Influence of the metal center and linker on the intracellular distribution and biological activity of organometal–peptide conjugates

Abstract

Organometallic complexes conjugated to cell-penetrating peptides (CPPs) are promising systems for diagnostic imaging and therapeutic applications in human medicine. Recently, we reported on the synthesis of cymantrene(CpMn(CO)(3))-CPP conjugates with biological activity on different cancer cell lines. However, the precise mechanism of cytotoxicity remained elusive in these studies. To investigate the role of the metal center and the linker between the CpM(CO)(3) moiety and the peptide, a number of derivatives with manganese replaced by rhenium and the keto linker originally used substituted by a methylene group were prepared and fully characterized by (1)H NMR spectroscopy, infrared spectroscopy, electrospray ionization mass spectrometry, and elemental analysis as well as X-ray structure determination. The organometal-peptide conjugates as well as carboxyfluorescein-labeled derivatives thereof were prepared by solid-phase peptide synthesis, purified by high-performance liquid chromatography, and analyzed by mass spectrometry. Fluorescence microscopy studies of MCF-7 human breast cancer cells revealed an efficient cellular uptake and pronounced nuclear localization of the bioconjugates with the methylene linker compared with systems with the keto group. In addition, the latter also showed a higher cytotoxicity. In contrast, the variation of the metal center from manganese to rhenium had a negligible effect. The structure-activity relationships determined in the present work will aid in the further tuning of the biological activity of organometal-peptide conjugates.

Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery

“…We were able to successfully apply sC18 for tumor imaging by conjugation with a metal chelator and a tumor-homing agent, which accumulates in hypoxic tissue [10]. Furthermore, we reported on the delivery of functionalized cyclopentadienyl manganese tricarbonyl (cymantrene) complexes with the help of sC18, which lead to significant induction of cytotoxicity in tumor cells [11–13], which was even more pronounced after introduction of an enzymatic cleavage site [12]. However, the aim of the present study was to investigate whether the cytotoxic effect of these organometallic complexes can be further increased by conjugating them to a dimeric variant of sC18, (sC18) 2 , since previous studies demonstrated improvement of the delivery of various kinds of cargo by CPP oligomerization [14–15].…”

A rhenium tris-carbonyl derivative as a single core multimodal probe for imaging (SCoMPI) combining infrared and luminescent properties

“…Other metal-CO derivatives have been found to be accumulated in specific organelles. 10,11,13,[28][29][30] These various locations show that these probes can be delivered to different cell-compartments depending on their appended moiety, which is a valuable property for imaging applications. 13 Since infrared and luminescence spectroscopies are complementary for bio-detection and bio-imaging, IR-luminescent (L)Re(CO) 3 SCoMPIs are of great potential and their multiple modalities open up wide prospects for cross-correlative studies in biological media.…”

Insertion of organometallic moieties into peptides and peptide nucleic acids using alternative “click” strategies

“…Such a fragmentation was already reported for similar biomolecules. 30 As further confirmation of the identity of the compound, the IR spectrum of 3A showed the vibrations of the CuO at 1927 and 2017 cm −1 . When the Fc precursor B was used as a reaction substrate, lower yields were observed for both the amino acid and the peptide labelling reactions.…”