Identification of the Structural Determinants for Anticancer Activity of a Ruthenium Arene Peptide Conjugate |
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Authors: | Dr Samuel M Meier Maria Novak Dr Wolfgang Kandioller Dr Michael A Jakupec Prof?Dr Vladimir B Arion Prof?Dr Nils Metzler‐Nolte Prof?Dr Bernhard K Keppler Prof?Dr Christian G Hartinger |
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Institution: | 1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria);2. Research Platform “Translational Cancer Therapy Research”, University of Vienna, Waehringer Strasse 42, 1090 Vienna (Austria);3. Inorganic Chemistry I–Bioinorganic Chemistry, Faculty of Chemistry and Biochemistry, Ruhr‐University Bochum, Universit?tsstrasse 150, 48801 Bochum (Germany);4. School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142 (New Zealand) |
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Abstract: | Organometallic Ru(arene)–peptide bioconjugates with potent in vitro anticancer activity are rare. We have prepared a conjugate of a Ru(arene) complex with the neuropeptide Leu5]‐enkephalin. Chlorido(η6‐p‐cymene)(5‐oxo‐κO‐2‐{(4‐(N‐tyrosinyl‐glycinyl‐glycinyl‐phenylalanyl‐leucinyl‐NH2)propanamido]‐1H‐1,2,3‐triazol‐1‐yl)methyl}‐4H‐pyronato‐κO)ruthenium(II)] ( 8 ) shows antiproliferative activity in human ovarian carcinoma cells with an IC50 value as low as 13 μM , whereas the peptide or the Ru moiety alone are hardly cytotoxic. The conjugation strategy for linking the Ru(cym) (cym=η6‐p‐cymene) moiety to the peptide involved N‐terminal modification of an alkyne‐Leu5]‐enkephalin with a 2‐(azidomethyl)‐5‐hydroxy‐4H‐pyran‐4‐one linker, using CuI‐catalyzed alkyne–azide cycloaddition (CuAAC), and subsequent metallation with the Ru(cym) moiety. The ruthenium‐bioconjugate was characterized by high resolution top‐down electrospray ionization mass spectrometry (ESI‐MS) with regard to peptide sequence, linker modification and metallation site. Notably, complete sequence coverage was obtained and the Ru(cym) moiety was confirmed to be coordinated to the pyronato linker. The ruthenium‐bioconjugate was analyzed with respect to cytotoxicity‐determining constituents, and through the bioconjugate models {2‐(azidomethyl)‐5‐oxo‐κO‐4H‐pyronato‐κO}chloride (η6‐p‐cymene)ruthenium(II)] ( 5 ) and chlorido(η6‐p‐cymene){5‐oxo‐κO‐2‐((4‐(phenoxymethyl)‐1H‐1,2,3‐triazol‐1‐yl]methyl)‐4H‐pyronato‐κO}ruthenium(II)] ( 6 ) the Ru(cym) fragment with a triazole‐carrying pyronato ligand was identified as the minimal unit required to achieve in vitro anticancer activity. |
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Keywords: | antitumor agents bioorganometallic chemistry mass spectrometry peptide bioconjugates ruthenium complexes |
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