ChemBioChem 2015-06-15

Peptide Bioconjugates of Electron-Poor Metallocenes: Synthesis, Characterization, and Anti-Proliferative Activity.

Marcus Maschke, Jens Grohmann, Claudia Nierhaus, Max Lieb, Nils Metzler-Nolte

Index: ChemBioChem. 16 , 1333-42, (2015)

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Abstract

We report the synthesis of metallocene compounds Cp2 M with two different electron-withdrawing substituents on both cyclopentadienyl rings (hexafluoroacetone (HFA) and chlorobenzoyl (1-5); HFA and COOH (6 and 7), M=Fe or Ru). The COOH-containing derivatives were used to synthesize peptide bioconjugates with enkephalin (8 and 9) and neurotensin (10 and 11) as well as fluorescein-labeled neurotensin (12). All the molecules were fully characterized, including X-ray structures for 6 and 7. The physicochemical properties (lipophilicity and electrochemistry) and cytotoxicity on MCF-7, HT-29, and PT-45 cancer cells were evaluated for selected compounds. Electrochemical investigation by cyclic voltammetry revealed that all bis-substituted metallocenes are up to 300 mV harder to oxidize compared to the monosubstituted 2-ferrocenylhexafluoropropan-2-ol (FcHFA: Δ${E{{{\rm f}\hfill \atop 0\hfill}}}$=214 mV; disubstituted derivatives: up to Δ${E{{{\rm f}\hfill \atop 0\hfill}}}$=512 mV; both vs. FcH(0/+) ). For the bis-substituted compounds, log P determinations by RP-HPLC showed increased lipophilicity in comparison to the monosubstituted FcHFA and RcHFA. Cellular uptake was investigated by fluorescence microcopy, and this revealed endosomal entrapment for 12. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.