Influence of the metal complex-to-peptide linker on the synthesis and properties of bioactive CpMn(CO)3 peptide conjugates

Abstract

By combining organometallic groups and peptides, a large number of conjugates with interesting new biological properties can be prepared. Especially, attachment to cell-penetrating peptides (CPP) that act as efficient cell delivery vehicles has come to the fore. However, the presence of the metal moiety in such systems can interfere with standard conjugate synthesis procedures which therefore need to be optimized for every new compound. In this work, we report on the preparation of six new cymantrene-sC18 peptide bioconjugates that were prepared by solid phase peptide synthesis (SPPS) techniques. The cymantrene complexes were chosen for their different linker to the peptide, to study the influence of the linker group on cellular uptake and cell viability of the conjugates. Interestingly, the attachment of the metal complex leads to a non-standard cleavage of the Rink amide linker used in the SPPS protocol under trifluoroacetic acid (TFA) treatment, resulting in peptide amides that are N-alkylated at the C-terminus. Furthermore, we found that depending on the type of cymantrene moiety attached, the formation of reactive carbocations which result from decomposition of the resin linker is facilitated and can alkylate the metal complex moiety. Both effects were analyzed by MS/MS studies and cleavage mixtures for efficient elimination of this byproduct formation were identified. Moreover, initial biological testing of the cytotoxicity of one of the bioconjugates gave promising results. Concentration-dependent cell viability studies of Cym1-sC18 on human MCF-7 breast adenocarcinoma cells gave an IC(50) value of 59.8 (+/- 6.7) microM and demonstrate their potential in anticancer chemotherapy.

Carbon monoxide – physiology, detection and controlled release

“…Carbohydrates and peptides can enhance water solubility, 179 biocompatibility and even biodistribution to certain tissues. 174,180,181 Morpholino groups may provide an amphiphilic character to the CORM. Solubility, membrane permeation and the pharmacokinetic profile may be controlled by terminal charged groups, such as amino, carboxylate groups and fluorine moieties.…”

Polymer Conjugates of Photoinducible CO‐Releasing Molecules

“…[52][53][54] Therefore, we tested the cytotoxicity of the compounds 1-3, P1, P2 and Mn(CO) 3 @P1/2 in Hct116 human colon carcinoma and HepG2 human hepatoma cells and compared them to the cytotoxicity of tricarbonyldichloridoruthenium(II) dimer ([Ru 2 (CO) 6 Cl 4 ], CORM-2). The compounds 1, 2 and Mn(CO) 3 @P1 do not show any significant cytotoxicity in the dark or when irradiwww.eurjic.orgated.…”

Cellular impact and selectivity of half-sandwich organorhodium(III) anticancer complexes and their organoiridium(III) and trichloridorhodium(III) counterparts

“…Analogous trichloridorhodium(III) complexes of the type mer-[RhCl 3 (DMSO)(phen*)] were studied for comparison purposes. An alternative approach to augmenting the biological activity of organometallic complexes is to attach one of their ligands to a cell-penetrating peptide (CPP) that can then facilitate the transport of the metal fragment of the resulting bioconjugate into target tumor cells [20,21]. Dppz complex 1 [22] (Scheme 1) was attached to a CPP as part of the present work.…”