Protease-Activatable Organometal−Peptide Bioconjugates with Enhanced Cytotoxicity on Cancer Cells

Abstract

Over the past years, numerous promising new metalorganic lead structures have been developed exhibiting highly active cytostatic properties. However, the efficiency of such chemotherapeutics in the treatment of tumors is often limited by their low therapeutic index due to their short half-life, lack of tumor selectivity, and associated side effects. Furthermore, the membrane barrier often restricts their cellular uptake by passive diffusion. In this contribution, we describe the synthesis, cellular uptake, and biologic activity of a series of cymantrene-peptide conjugates. Cymantrene CpMn(CO)(3) is a robust organometallic group, which is stable in air and water and easy to functionalize. In this work, some new cymantrene derivatives with different linkers between the half-sandwich complex and the carboxylate group were attached to the cell-penetrating peptide sC18 that should act as a transporter for the metal moiety. All conjugates were characterized for their cytotoxic activity on human breast adenocarcinoma cells (MCF-7) and human colon carcinoma cells (HT-29). We found that bioconjugates bearing two cymantrene groups were more active than the monofunctionalized ones. By the introduction of a cathepsin B cleavage site next to the organometallic group, the biologic activity could be in increased even further. Fluorescence microscopy studies and apoptosis assays gave preliminary hints on the mode of action of these systems.

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

“…25 In recent years, several coordination or organometallic complexes have also been conjugated to carrier molecules such as receptor-binding peptides or known delivery peptides to improve both cellular uptake to cancer cells and cytotoxic activity of the metal-based drug. 26,27,28,29,30,31,32,33 Herein we report on the use of conjugates between octreotide and several metal complexes as new chemotherapeutic agents. In particular, the synthesis of hybrid compounds between the dicarba analogue of octreotide (2) and platinum(II), ruthenium(II) and osmium(II) metal complexes has been accomplished by efficient solid-phase procedures (compounds 3-6 in Chart 1).…”

Specific Targeting of Hypoxic Tumor Tissue with Nitroimidazole–Peptide Conjugates

“…[8,9] Using this method, we recently reported the successful and efficient delivery of nanocrystals, [10] oligonucleotides, [11] gallium complexes [12] and bioactive metal complexes [13][14][15][16] into cancer, as well as primary cells. However, while CPPs provide a tool through which cell-impermeable compounds can reach intracellular targets, one of their major drawbacks is their lack of selectivity towards different cell lines.…”

Peptide-mediated vectorization of metal complexes: conjugation strategies and biomedical applications

“…Moreover, Neundorf and co-workers reported the attachment of cymantrene (CpMn(CO) 3 ) carboxylic acid derivatives to the cellpenetrating peptide GLRKRLRKFRNKIKEK-NH 2 (sC18), which was previously identified by the same authors (Figure 5b). 58 (Figure 5c). 59 The resulting conjugates retained the iron binding abilities and the antioxidant properties of DFO, and showed an enhanced cell internalization capacity.…”