Tuning a modular system - synthesis and characterisation of a boron-rich s-triazine-based carboxylic acid and amine bearing a galactopyranosyl moiety.

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.

Enlargement of a Modular System-Synthesis and Characterization of an s-Triazine-Based Carboxylic Acid Ester Bearing a Galactopyranosyl Moiety and an Enormous Boron Load.

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.

Modular triazine-based carborane-containing carboxylic acids - synthesis and characterisation of potential boron neutron capture therapy agents made of readily accessible building blocks.

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.

Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation.

Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM-1 receptor (AM1 R). A disulfide-bonded ring structure consisting of six amino acids between Cys16 and Cys21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/t-Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam-based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether-based mimetics to be well accepted with full AM1 R activity. While a reduced selectivity over the calcitonin gene-related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild-type-like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1 R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM.

A stable meta-carborane enables the generation of boron-rich peptide agonists targeting the ghrelin receptor.

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.

Jietacins, azoxy antibiotics with potent nematocidal activity: Design, synthesis, and biological evaluation against parasitic nematodes.

Jietacins, an azoxy antibiotic class of chemicals, were isolated from the culture broth of Streptomyces sp. KP-197. They have a unique structural motif, including a vinyl azoxy group and a long acyclic aliphatic chain, which is usually branched but non-branched in the case of jietacin C. During a drug discovery program, we found that jietacins display potent anthelmintic activity against parasitic nematodes and that jietacin A has a moderate or low acute toxicity (LD50 > 300 mg/kg) and no mutagenic potential in a mini Ames screen. This suggests that jietacins have potential for drug discovery research. In order to create a novel anthelmintic agent, we performed design, synthesis, and biological evaluation of jietacin derivatives against parasitic nematodes. Of these derivatives, we found that a fully synthesized simplified derivative exhibited better anthelmintic activity against three parasitic nematodes than natural jietacins. In addition, it had a better efficacy in vivo through oral administration against a mouse nematode. This indicated that the azoxy motif could prove useful as a template for anthelmintic discovery, possibly creating a class of anthelmintic with novel skeletons, a potential new mode of action, and providing further insight for rational drug design.

5-O-Mycaminosyltylonolide antibacterial derivatives: design, synthesis and bioactivity.

Tylosin is a 16-membered macrolide broad-spectrum antibiotic that has an important role in veterinary medicine, active against Gram-positive and a restricted range of Gram-negative bacteria. We synthesized 15 types of tylosin-related derivatives by chemical modification and evaluated them against mastitis pathogens. Among them, 20-deoxy-20-{N-methyl-N-[1-(3-quinolyl)-1H-1,2,3-triazol-4-yl]methylamino}-5-O-mycaminosyltylonolide 2f and 20-deoxy-20-{N-benzyl-N-[1-(3-quinolyl)-1H-1,2,3-triazol-4-yl]methylamino}-5-O-mycaminosyltylonolide 2k were found to not only expand their antibacterial impact to include Gram-negative bacteria, such as Escherichia coli and Klebsiella pneumoniae, but also to retain or increase antibacterial activity against Gram-positive bacteria, such as Staphylococcus aureus and Streptococcus uberis in comparison with the parent tylosin.

[Political issues in internal medicine in Europe. A position paper]. / Pozycja i przyszlosc medycyny wewn trznej w Europie. Prezentacja naszego stanowiska.

What will be the future of internal medicine in Europe? Because of rapidly growing concerns regarding the position of internal medicine in many European countries, the European Federation of Internal Medicine (EFIM) has established a working group to analyze the situation. Being well aware of the variation in working practices in the different countries, the members of the group used an "all-European" approach to answer the following questions: Are there problems for internal medicine? If so, what are these problems and why? Why do the health care systems in the European countries need internal medicine? Why do patients need internal medicine? What needs to be done? Internal medicine is the modern, clinical, and scientific medical discipline that is responsible for the care of adult patients with one or more complex, acute, or chronic illnesses. Internal medicine is the cornerstone of an integrated health care delivery service that is needed today. Decision-makers in politics and hospitals, insurers, journalists, and the general public need a better understanding of what internal medicine can offer to the health care system and to the individual patient.

Political issues in internal medicine in Europe.

What will be the future of Internal Medicine in Europe? Because of rapidly growing concerns regarding the position of Internal Medicine in many European countries, the European Federation of Internal Medicine has established a working group to analyze the situation. Being well aware of the variation of working practices in the different countries, the members of the group used an "all-European" approach to answer the following questions: Are there problems for Internal Medicine, what problems and why? Why do the health care systems of the European countries need Internal Medicine? Why do the patients need Internal Medicine? What needs to be done? Internal Medicine is the modern, clinical and scientific medical discipline taking care of adult patients with one or more complex, acute or chronic illnesses. Internal Medicine is the cornerstone of integrated health care delivery service that is needed today. Decision-makers in politics and hospitals, insurers, journalists and the general public need a better understanding of what Internal Medicine can offer to the health care system and to the individual patient.

Political issues in internal medicine in Europe. A position paper.

What will be the future of internal medicine in Europe? Because of rapidly growing concerns regarding the position of internal medicine in many European countries, the European Federation of Internal Medicine (EFIM) has established a working group to analyze the situation. Being well aware of the variation in working practices in the different countries, the members of the group used an "all-European" approach to answer the following questions: Internal medicine is the modern, clinical, and scientific medical discipline that is responsible for the care of adult patients with one or more complex, acute, or chronic illnesses. Internal medicine is the cornerstone of an integrated health care delivery service that is needed today. Decision-makers in politics and hospitals, insurers, journalists, and the general public need a better understanding of what internal medicine can offer to the health care system and to the individual patient.