title: Peptide Bioconjugates of Electron-Poor Metallocenes: Synthesis, Characterization, and Anti-Proliferative Activity.
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.
authors.affiliation: Lehrstuhl für Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum (Germany).
authors.forename: Marcus
authors.initials: M
authors.lastname: Maschke
authors.affiliation: Lehrstuhl für Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum (Germany).
authors.forename: Jens
authors.initials: J
authors.lastname: Grohmann
authors.affiliation: Lehrstuhl für Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum (Germany).
authors.forename: Claudia
authors.initials: C
authors.lastname: Nierhaus
authors.affiliation: Lehrstuhl für Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum (Germany).
authors.forename: Max
authors.initials: M
authors.lastname: Lieb
authors.affiliation: Lehrstuhl für Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum (Germany). nils.metzler-nolte@rub.de.
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004745:Enkephalins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D009496:Neurotensin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004745:Enkephalins; D009942:Organometallic Compounds; D010455:Peptides; C013108:metallocene; D009496:Neurotensin
keywords: fluorinated metallocenes; medicinal organometallic chemistry; metal-based drugs; metallocenes; solid-phase synthesis