Konjugate aus Übergangsmetallverbindungen und Biomolekülen als Bausteine für Biosensoren mit spektroskopischer und elektrochemischer Detektion

Meine Gruppe nutzt die besonderen spektroskopischen und chemischen Eigenschaften von Übergangsmetallverbindungen für die Detektion und Modifizierung von Biomolekülen wie bioaktiven Peptiden und DNA-Analoga. Anwendungen unserer Biokonjugate umfassen die med. Diagnostik und DNA-Analytik, insbesondere auf sog. DNA Chips. Die folgenden Detektionsmethoden sind besonders auf Metallkomplexe zugeschnitten: • Optische Spektroskopie (incl. Fluoreszenzspektroskopie) • Infrarot-Spektroskopie (u. a. als Carbonyl Metallo Immuno Assay CMIA) • Elektrochemische Detektion Von diesen ist die elektrochemische Detektion besonders für das moderne high-throughput Screening mithilfe von Biochips geeignet und stellt naturgemäß einen Schwerpunkt unserer Arbeiten dar, da eine Vielzahl von Metallkomplexen in einem geeigneten Potentialbereich reversibel oxdierbar bzw. reduzierbar ist. Die experimentelle Herausforderung liegt darin, luft- und wasserstabile Metallkomplexe mit geeigneten Eigenschaften zu identifizieren und milde, biokompatible Methoden für die Synthese der Biokonjugate mit diesen Metallkomplexen zu entwickeln. Offensichtlich können nur solche synthetischen Methoden verwendet werden, die mit den diversen funktionellen Gruppen in Biomolekülen (Amine, Amide, Alkohole, Thiole, etc.) kompatibel sind. Auf dem Poster präsentieren wir neue synthetische Methoden für die Markierung von Biomolekülen mit Übergangsmetallverbindungen, die in meiner Gruppe entwickelt wurden, sowie die Charakterisierung der Konjugate an ausgewählten Beispielen. In einem weiteren Projekt untersuchen wir Metallkomplexe von PNA (Peptide Nucleic Acid) auf ihre mögliche Verwendung in Biosensoren. PNA wurde 1991 von Nielsen und Buchardt entwickelt und ist ein DNA-Analogon mit ausgezeichneten Eigenschaften für Anwendungen in der Molekularbiologie und Biotechnologie. Die Wechselwirkung eines PNA-Ruthenium-Konjugates 2 mit komplementärer DNA und PNA wurde mittels UV-Schmelztemperatur und CD-Spektroskopie untersucht

Iridium(I) Compounds as Prospective Anticancer Agents: Solution Chemistry, Antiproliferative Profiles and Protein Interactions for a Series of Iridium(I) N-Heterocyclic Carbene Complexes

Aseries of structurally related mono-and bis-NHC–iridium(I) (NHC:N-heterocyclic carbene) complexeshave been investigatedfor their suitability as potential anti-cancer drugs.Their spectral behaviour in aqueous buffersunder physiologic al-like conditions and their cytotoxicityagainstthe cancercell lines MCF-7 and HT-29are reported.Notably,almostall complexes exhibit significant cytotoxic ef-fects towards both cancer cell lines. In general,the cationicbis-carbene complex es show higherstabilityand greater an-ticanceractivity than their neutral mono-carbene analogueswith IC50valuesinthe high nanomolar range.Furthermore,to gain initialmechanistic insight, the interactions of theseiridium(I)–NHC complexes with two model proteins,namelylysozyme and cytochrome c, were exploredbyHR-ESI-MSanalyses. The different protein metalation patternsofthecomplexes can be roughlyclassified into two distinctgroups. Those interactions give us afirst idea about the pos-sible mechanism of action of this class of compounds. Over-all, our findings show that iridium(I)–NHC complexesrepre-sent very interesting candidates forfurther development asnew metal-based anticancer drugs

Metal and Substituent Influence on the Cytostatic Activity of Cationic Bis‐cyclometallated Iridium and Rhodium Complexes with Substituted 1,10‐Phenanthrolines as Ancillary Ligands

Synthesis and characterization of the new cyclometalated complex salts [Rh(ptpy)2(5.6‐dimethyl‐1,10‐phenanthroline)]PF6 (1a) [Rh(ptpy)2(2.9‐dimethyl‐4.7‐diphenyl‐1,10‐ phenanthroline)]PF6 (2a), [Rh(ptpy)2(5‐amino‐1,10‐phenanthroline)] PF6 (3a), and [M(ptpy)2 (pyrazino‐[2.3‐f]‐1,10‐phenanthroline)]PF6 (M = Rh, 4a; M = Ir, 4b), (ptpy = 2‐(p‐tolyl)pyridinato) are described. The molecular structures of compounds 1b and 4a in the solid state were determined by single‐crystal X‐ray diffraction. All these compounds and their already known Iridium counterparts 1b – 3b display significant cytotoxicity against human cancer cell lines MCF‐7 (human breast adenocarcinoma) and HT‐29 (colon adenocarcinoma) with IC50 values in the low micromolar range

Ru(ii)-Peptide bioconjugates with the cppH linker (cppH = 2-(2'-pyridyl)pyrimidine-4-carboxylic acid): synthesis, structural characterization, and different stereochemical features between organic and aqueous solvents

Three new Ru(ii) bioconjugates with the C-terminal hexapeptide sequence of neurotensin, RRPYIL, namely trans,cis-RuCl2(CO)2(cppH-RRPYIL-\u3baNp) (7), [Ru([9]aneS3)(cppH-RRPYIL-\u3baNp)(PTA)](Cl)2 (8), and [Ru([9]aneS3)Cl(cppH-RRPYIL-\u3baNp)]Cl (11), where cppH is the asymmetric linker 2-(2'-pyridyl)pyrimidine-4-carboxylic acid, were prepared in pure form and structurally characterized in solution. The cppH linker is capable of forming stereoisomers (i.e. linkage isomers), depending on whether the nitrogen atom ortho (No) or para (Np) to the carboxylate on C4 in the pyrimidine ring binds the metal ion. Thus, one of the aims of this work was to obtain pairs of stereoisomeric conjugates and investigate their biological (anticancer, antibacterial) activity. A thorough NMR characterization clearly indicated that in all cases exclusively Np conjugates were obtained in pure form. In addition, the NMR studies showed that, whereas in DMSO-d6 each conjugate exists as a single species, in D2O two (7) or even three if not four (8 and 11) very similar stable species form (each one corresponding to an individual compound). Similar results were observed for the cppH-RRPYIL ligand alone. Overall, the NMR findings are consistent with the occurrence of a strong intramolecular stacking interaction between the phenol ring of tyrosine and the pyridyl ring of cppH. Such stacking interactions between aromatic rings are expected to be stronger in water. This interaction leads to two stereoisomeric species in the free cppH-RRPYIL ligand and in the bioconjugate 7, and is somehow modulated by the less symmetrical Ru coordination environments in 8 and 11, affording three to four very similar species

Cytotoxic Activities of Bis-cyclometalated M(III) Complexes (M=Rh, Ir) Containing 5-substituted 1,10-Phenanthroline or 4,4'-substituted 2,2'-Bipyridine Ligands

The synthesis and characterization of eight new bis-cyclometalated compounds [M(ptpy)(2)(NN)]PF6 (ptpy=2-(p-tolyl)pyridinato;NN=5-chloro-1,10-phenanthroline: M=Rh, 1;M=Ir, 2);NN=5-methyl-1,10-phenanthroline: M=Rh, 3;M=Ir, 4;NN=4,4'-diphenyl-2,2'-bipyridine: M=Rh, 5;M=Ir, 6;NN=4,4'-diamino-2,2'-bipyridine: M=Rh, 7;M=Ir, 8) are described. All compounds were characterized by spectroscopic means. Additionally, the molecular structures of compounds 4, 5, 6, and 8 in the crystal were determined by single-crystal X-ray diffraction studies. To explore the cytotoxic properties of all new eight compounds, colorimetric assays (MTT assay) against prominent cancer cell lines, MCF-7 and HT-29, were performed. The determined IC50 values are in the low micromolar range, between 1.3-5.6 mu M. The most effective compounds are 1 and 2 with 5-chloro-substituted phenanthroline ligands, whereas the diamino-substituted bipyridine ligands (5 and 6) are the least cytotoxic compounds. The tested complexes showed a significant increase in cytotoxicity, up to 25-fold increase in MCF-7 cancer cells, and up to 60-fold increase in the HT-29 cell line compared to the established anticancer compound cisplatin under identical conditions

Cytotoxic Activities of Half‐sandwich M(III) Complexes (M=Rh, Ir) Bearing Chloro‐substituted Bidentate‐coordinated Phenanthroline or Terpyridine Ligands

The synthesis and characterization of four compounds [M(η5-C5Me5)(N^N)Cl]PF6 [N^N=4,7-dichloro-1,10-phenanthroline with M=Rh, 1, and M=Ir, 2, and N^N=4'-(4-chlorophenyl)-2,2':6',2''-terpyridine in the κ2N,N'-coordination mode with M=Rh, 3, and M=Ir, 4] are described. All compounds were characterized by spectroscopic means and their molecular structures in the crystal were confirmed by single-crystal X-ray diffraction studies. The cytotoxicity of all compounds was evaluated by MTT assay against the three cancer cell lines HeLa (cervical carcinoma), HT-29 (colon adenocarcinoma) and MCF-7 (human breast adenocarcinoma). The complexes 3 and 4 display promising activity with IC50 values of 1 μM. The rhodium(III) complex 1 also shows highly improved cytotoxicity compared to cisplatin against the cancer cell lines HT-29 and MCF-7. In contrast to this, the iridium(III) complex 2 is even less active against the HeLa cell line than cisplatin

Cytotoxic Activity of Some Half‐sandwich Rhodium(III) Complexes Containing 4,4’‐disubstituted‐2,2’‐bipyridine Ligands

The synthesis and characterization of three compounds [Rh(η5-C5Me5)Cl(N^N)]PF6 (N^N=4,4’-disubstituted-2,2’-bipyridines, 1–3) are described. The cationic complexes contain the bidentate ligands N^N=4,4'-di-tert-butyl-2,2'-bipyridine (1), N^N=4,4'-dinonyl-2,2'-bipyridine (2) and N^N=4,4'-diamino-2,2'-bipyridine (3). The complex salts were obtained by the bridge-splitting reaction from the precursor [{Rh(η5-C5Me5)(μ-Cl)Cl}2] and subsequent salt metathesis affording their corresponding hexafluorido phosphate salts. All compounds were characterized by elemental analysis and spectroscopic means. Additionally, the molecular structure of compound 3 in the solid was determined by a single-crystal X-ray diffraction study. The cytotoxicity of all three compounds was examined by MTT assay against two cancer cell lines – HT-29 (colon adenocarcinoma) and MCF-7 (human breast adenocarcinoma) - and normal human fibroblast cells (GM5657T). Compound 1 has moderate cytotoxicity against both cell lines, while compound 2 is seven to nine times more cytotoxic than cisplatin against MCF-7 and HT-29, respectively. In contrast to cisplatin, both compounds are more active against cancer cells than fibroblasts, thus showing some cancer selectivity

Novel π-Extended Quinazoline-Ferrocene Conjugates: Synthesis, Structure, and Redox Behavior

Novel ferrocene conjugates of tricyclic quinazoline derivatives are prepared by condensation of active C-6 methylene groups of mackinazolinones with ferrocenecarbaldehyde. Following this route the conjugated parent alkaloid as well as derivatives with nitro, amino, and alkanoylamino groups at C-2 were attached at the ferrocene moiety, thereby significantly extending the delocalized π system. In addition, the parent compound was subjected to the reaction with ferrocene-1,1'-dicarbaldehyde, giving rise to the symmetrical and unsymmetrical double condensation products – 1,1'-disubstituted ferrocene derivatives, which bear two alkaloid substituents. Some of the compounds obtained were subjected to X-ray crystallographic analyses. The influence of the substituents at C-2 through the extended conjugated π system on the iron atom is reflected by results of cyclovoltammetric measurements

Cytotoxic Activities of Bis-cyclometalated Iridium(III) Complexes Containing Chloro-substituted kappa N-2-terpyridines

The synthesis and characterization of two new bis-cyclometalated compounds [Ir(ptpy)(2)(kappa N-2-terpy-C6H4Cl-p)]PF6 [terpy-C6H4Cl-p=4'-(4-chlorophenyl)-2,2':6',2''-terpyridine, (1)], and [Ir(ptpy)(2)(kappa N-2-terpy-Cl)]PF6 [terpy-Cl=4'-chloro-2,2':6',2''-terpyridine, (2);ptpy=2-(p-tolyl)pyridinato)] are described. The molecular structures of compounds 1 and 2 in the crystal were determined by single-crystal X-ray diffraction. 1 crystallized from dichloromethane/methanol/iso-hexane in the monoclinic space group P2/(n) and 2 from the same mixture of solvents in the triclinic space group P(-)1. Photophysical investigations on 1 and 2 revealed broad unstructured luminescence in the red spectral region with the emission maxima in dichloromethane at 620 and 630 nm respectively. To explore cytotoxic properties of compounds 1 and 2, a colorimetric assay (MTT assay) against prominent cancer cell lines, MCF-7 and HT-29, was performed. The determined IC50 values are in the low micromolar range (2-3 mu M). In comparison to cisplatin, the tested complexes 1 and 2 exhibit up to >20-fold (MCF-7) and >40-fold (HT-29) increase in biological activity