Exploring Alternative Pathways to Target Bacterial Type II Topoisomerases Using NBTI Antibacterials: Beyond Halogen-Bonding Interactions.

Novel bacterial topoisomerase inhibitors (NBTIs) are a new class of antibacterial agents that target bacterial type II topoisomerases (DNA gyrase and topoisomerase IV). Our recently disclosed crystal structure of an NBTI ligand in complex with DNA gyrase and DNA revealed that the halogen atom in the para position of the phenyl right hand side (RHS) moiety is able to establish strong symmetrical bifurcated halogen bonds with the enzyme; these are responsible for the excellent enzyme inhibitory potency and antibacterial activity of these NBTIs. To further assess the possibility of any alternative interactions (e.

Development of the Tc-Labelled SST Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study.

Broad availability and cost-effectiveness of Mo/Tc generators worldwide support the use, and thus the development, of novel Tc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST) antagonists, mainly due to their superiority in SST-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a Tc-labelled SST antagonist, [Tc]Tc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial.

Selection of the First Tc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates.

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project "TECANT" two Tc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2).

Radiolabelled CCK R Antagonists Containing PEG Linkers: Design, Synthesis and Evaluation.

The cholecystokinin-2/gastrin receptor (CCK R) is considered a suitable target for the development of radiolabelled antagonists, due to its overexpression in various tumours, but no such compounds are available in clinical use. Therefore, we designed novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated ligands based on CCK R antagonist Z360/nastorazepide. As a proof of concept that CCK R antagonistic activity can be retained by extending the Z360/nastorazepide structure using suitable linker, we present herein three compounds containing various PEG linkers synthesised on solid phase and in solution.

CCKR antagonists: from SAR to clinical trials.

The widespread involvement of the cholecystokinin-2/gastrin receptor (CCKR) in multiple (patho)physiological processes has propelled extensive searches for nonpeptide small-molecule CCKR antagonists. For the past three decades, considerable research has yielded numerous chemically heterogeneous compounds. None of these entered into the clinic, mainly because of inadequate biological effects.

Cyclohexyl amide-based novel bacterial topoisomerase inhibitors with prospective GyrA-binding fragments.

Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of bacterial topoisomerase II inhibitors that are gaining more and more importance mainly because of their excellent antibacterial activity, as well as their lack of cross-resistance to quinolones. Described here is the synthesis and biological evaluation of a tiny series of new virtually assembled NBTIs containing synthetically feasible right-hand side fragments capable of binding the GyrA subunit of the bacterial DNA gyrase-DNA complex. NBTI variants with incorporated 1-phenylpyrazole right-hand side moiety show suitable antibacterial activity against Gram-positive , with confirmed selectivity over the human topoisomerase IIα enzyme.