Laurent Bischoff

Inhibition of vasopressinergic neurons by central injection of a specific aminopeptidase A inhibitor.

THE brain angiotensin (Ang) system plays an important role in the central control of vasopressin release. Using EC33, a selective aminopeptidase A inhibitor which blocks the metabolism of Ang II in Ang III, we previously reported that vasopressin release was under the control of Ang III and not Ang II. To determine accurately the action of EC33, the effects of intracerebroventricular injection of Ang peptides or EC33 on extracellular unit activity of vasopressinergic neurons in the supraoptic nucleus of urethane-anaesthetized rats were examined. Angiotensin II (15–30 ng) or Ang III (15 ng) increased the firing rate of all neurons tested. Conversely, EC33 (10 μg) reduced or completely abolished (30–60μg) the basal firing rate for 4–6 min in all eight neurons tested. EC33 (30 μg) also inhibited the activity induced by 30 ng Ang II. It was concluded that the observed activity of Ang II required its conversion to Ang III and that endogenous Ang III may exert a tonic control on the basal firing level of vasopressinergic neurons.

A Concise Synthesis of Lentiginosine Derivatives Using a Pyridinium Formation via the Mitsunobu Reaction

A four-step synthesis of (-)-lentiginosine and its epimers is described starting from 2-bromopyridine. The key step consisted of a quaternarization of a fully unprotected pyridinium-polyol unit using Mitsunobu methodology. Subsequent PtO(2)-catalyzed diastereoselective hydrogenation of the pyridinium ring proceeded smoothly and led to the expected dihydroxyindolizidines with excellent yields. This stereochemically flexible strategy has been illustrated by the concise total synthesis of non-natural products derivatives such as (-)-lentiginosine and its stereoisomers in high yields.

New family of peptidomimetics based on the imidazole motif.

Starting from amino acid esters, new peptidomimetics based on the imidazole scaffold were prepared. An efficient and rapid sequence consisting of two subsequent one-pot procedures was developed and applied to various aminoacids. As they provide more substitution patterns, these heterocyclic mimics are promising tools for structural and biological studies.

Ligand-Free Pd-Catalyzed and Copper-Assisted C–H Arylation of Quinazolin-4-ones with Aryl Iodides under Microwave Heating

A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.

SYNTHESIS OF (3S,4S)-4-HYDROXY-2,3,4,5-TETRAHYDROPYRIDAZINE-3-CARBOXYLIC ACID, COMPONENT OF LUZOPEPTIN A

Abstract The enantioselective synthesis of (3 S , 4 S )-4-hydroxy-2, 3, 4, 5-tetrahydropyridazine-3-carboxylic acid 1 is described. The two stereogenic centers in anti relationship are obtained by sequential enantio and chemoselective hydrogenation of β-ketoester in presence of chiral ruthenium catalyst and diastereoselective amination of β-hydroxyester with di t -butylazodicarboxylate.

Synthesis and biological evaluation of a novel 99mTc labeled 2-nitroimidazole derivative as a potential agent for imaging tumor hypoxia

Tumor hypoxia plays a major role in reducing the efficacy of therapeutic modalities like chemotherapy and radiation therapy in combating cancer. In order to target hypoxic tissues, a tripeptide ligand having a 2-nitroimidazole moiety, as a bioreductive species, was synthesized. The latter was radiolabeled with (99m)Tc for imaging hypoxic regions of tumors and was characterized by means of its rhenium analogue. The biodistribution and scintigraphic image of the corresponding (99m)Tc-complex showed accumulation in tumor and these results suggest that it could be a marker for imaging tumor hypoxia.

Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity

A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hydroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition. This article is part of a discussion meeting issue ‘Frontiers in epigenetic chemical biology’.

A Convenient One‐Pot Preparation of Stable Equivalents of Cyclobutane‐1,2‐dione and Cyclobutanetrione

Abstract A very short, high‐yielding, one‐pot procedure has been developed for the preparation of half‐protected cyclobutane‐1,2‐dione. This compound is much more stable than cyclobutane‐1,2‐dione itself and allowed further transformation to give diprotected cyclobutanetrione equivalents.

A first subnanomolar and in vivo active inhibitor of aminopeptidase A (EC 3.4.11.7)

Aminopeptidase A is a zinc metallopeptidase which specifically cleaves the N-terminal aspartate or glutamate of peptides. Thus, it is involved in the in vivo metabolism of CCK8 [1] and angiotensin II [2]. Previous studies [3] of the catalytic site of APA had led to the first selective inhibitor of this enzyme, i.e. the -aminothiol EC33 which presents a negatively charged residue in position and a thiol for an optimal chelation of the zinc ion. However, to further investigate the physiological role of APA, some new and more potent inhibitors of the general formula I were designed (Fig. 1) by exploration of the and subsites.