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J Med Chem ; 63(5): 2358-2371, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589041


G-protein-coupled receptors like the human Y1 receptor (hY1R) are promising targets in cancer therapy due to their high overexpression on cancer cells and their ability to internalize together with the bound ligand. This mechanism was exploited to shuttle boron atoms into cancer cells for the application of boron neutron capture therapy (BNCT), a noninvasive approach to eliminate cancer cells. A maximized number of carboranes was introduced to the hY1R-preferring ligand [F7,P34]-NPY by solid phase peptide synthesis. Branched conjugates loaded with up to 80 boron atoms per peptide molecule exhibited a maintained receptor activation profile, and the selective uptake into hY1R-expressing cells was demonstrated by internalization studies. In order to ensure appropriate solubility in aqueous solution, we proved the need for eight hydroxyl groups per carborane. Thus, we suggest the utilization of bis-deoxygalactosyl-carborane building blocks in solid phase peptide synthesis to produce selective boron delivery agents for BNCT.

Dalton Trans ; 49(1): 57-69, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31808482


Introduction of a bis(isopropylidene)-protected galactopyranosyl moiety in s-triazine-based boron-rich carboxylic acids and amines results in soluble and suitable coupling partners for tumour-selective biomolecules with applications as selective agents for boron neutron capture therapy (BNCT). Bearing either a carboxylic acid or primary amine as a functional group, these compounds are highly versatile and thus largely extend the possible coupling strategies with suitable biomolecules. Modification of the gastrin-releasing peptide receptor (GRPR) selective agonist [d-Phe6, ß-Ala11, Ala13, Nle14]Bn(6-14) with the carboxylic acid derivative yielded a bioconjugate with an optimal receptor activation and internalisation profile. This demonstrates the great potential of this approach for the development of novel boron delivery agents.

Dalton Trans ; 48(29): 10834-10844, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31246208


Based on a modular combination of s-triazine, the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12) and commercially available carboxylic acids, namely thioglycolic acid, glycine, and Nα-Boc-l-lysine, several carboxylic acid derivatives were synthesised and fully characterised. The thioglycolic acid derivative was introduced into a peptide hormone by solid phase peptide synthesis. High activity and selective internalisation into peptide receptor-expressing cells was observed. With a very high boron content of twenty boron atoms, these derivatives are interesting as selective Boron Neutron Capture Therapy (BNCT) agents.

J Pept Sci ; 24(10): e3119, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30168238


Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron-containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein-coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor-directed boron uptake. In this study, we present the generation of short, boron-rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super-agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta-carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron-loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin.

Boro/farmacologia , Peptídeos/síntese química , Receptores de Grelina/agonistas , Boro/química , Terapia por Captura de Nêutron de Boro , Portadores de Fármacos , Células HEK293 , Humanos , Oligopeptídeos/química , Peptídeos/química
Int J Mol Sci ; 18(4)2017 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-28379199


The ghrelin receptor (GhrR) is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound (S)-6-(4-bromo-2-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one ((S)-9) has been described as a GhrR ligand with high binding affinity. Here, we describe the synthesis of fluorinated derivatives, the in vitro evaluation of their potency as partial agonists and selectivity at GhrRs, and their physicochemical properties. These results identified compounds (S)-9, (R)-9, and (S)-16 as suitable parent molecules for 18F-labeled positron emission tomography (PET) radiotracers to enable future investigation of GhrR in the brain.

Proteínas de Transporte/metabolismo , Imagem Molecular/métodos , Pirimidinas/síntese química , Pirimidinas/metabolismo , Animais , Células CHO , Cricetulus , Halogenação , Humanos , Ligantes , Estrutura Molecular , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica , Pirimidinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo
ChemMedChem ; 10(9): 1564-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26149664


Peptide dendrimers are a class of molecules of high interest in the search for new antibiotics. We used microwave-assisted, copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC; "click" chemistry) for the simple and versatile synthesis of a new class of multivalent antimicrobial peptides (AMPs) containing solely arginine and tryptophan residues. To investigate the influence of multivalency on antibacterial activity, short solid-phase- synthesized azide-modified Arg-Trp-containing peptides were "clicked" to three different alkyne-modified benzene scaffolds to access scaffolds with one, two, or three peptides. The antibacterial activity of 15 new AMPs was investigated by minimal inhibitory concentration (MIC) assays on five different bacterial strains, including a multidrug-resistant Staphylococcus aureus (MRSA) strain. With ultrashort (2-3 residues) peptides, a clear synergistic effect of the trivalent display was observed, whereas this effect was not apparent with longer peptides. The best candidates showed activities in the low-micromolar range against Gram-positive MRSA. Surprisingly, the best activity against Gram-negative Acinetobacter baumannii was observed with an ultrashort dipeptide on the trivalent scaffold (MIC: 7.5 µM). The hemolytic activity was explored for the three most active peptides. At concentrations ten times the MIC values, <1 % hemolysis of red blood cells was observed.

Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Arginina/química , Química Click , Avaliação Pré-Clínica de Medicamentos/métodos , Hemólise/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida , Relação Estrutura-Atividade , Triptofano/química