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Peptide Bioconjugates of Electron‐Poor Metallocenes: Synthesis, Characterization, and Anti‐Proliferative Activity
Author(s) -
Maschke Marcus,
Grohmann Jens,
Nierhaus Claudia,
Lieb Max,
MetzlerNolte Nils
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500060
Subject(s) - chemistry , lipophilicity , cyclopentadienyl complex , combinatorial chemistry , cyclic voltammetry , neurotensin , peptide , electrochemistry , sonogashira coupling , ferrocene , metallocene , molecule , stereochemistry , medicinal chemistry , organic chemistry , receptor , biochemistry , electrode , neuropeptide , catalysis , palladium , polymer , polymerization
We report the synthesis of metallocene compounds Cp 2 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 .