Emmanuel Gras

Two functions, one molecule: a metal-binding and a targeting moiety to combat Alzheimer's disease.

It is estimated that Alzheimer’s disease (AD) strikes 5 % of people over the age of 65. In Western countries, this number was 15 % in the mid 1990s and is estimated to exceed 20 % in 2020. The increasing number of AD victims expected in the near future will place the healthcare system under increasing pressure. To date there is no disease-modifying therapy available. This clearly underlines the need to find new and more efficient medical treatments for AD. Alzheimer’s disease is a complex multifactorial neurodegenerative disease in which many genetic and environmental factors are involved. In this respect, drugs exhibiting several therapeutic activities that intervene in different biological functions in the development of AD seem to be very attractive. A variation of this concept is to add a targeting moiety that brings and concentrates the other moiety/ ies at its/their place of action, and thus potentially increases the drug’s efficiency and reduces its side effects. Such multitarget-directed molecules are expected to have a better therapeutic profile to combat such complex diseases. What are the preferred targets in AD? As the disease is multifactorial, there are several different processes linked to AD. Two of the most prominent ones are the processes leading to the two morphological hallmarks of AD: the aggregation of the peptide amyloid-b (Ab) to form amyloid plaques and the formation of neurofibrillary tangles (NFTs) by the hyperphosphorylated tau protein. In particular, the former one has been considered to be a central process and a relatively early event in the cascade process that leads to AD. A large number of researchers consider the so-called “amyloid cascade hypothesis” (Scheme 1) to be the key event in AD etiology. This hypothesis suggests that the mismetabolism of Ab and its amyloid-precursor protein (APP) is the initiating event in AD pathogenesis, and subsequently leads to the aggregation of Ab. The formation of Ab aggregates would instigate further pathological events, including the formation of NFTs and the disruption of synaptic connections; this would lead to a reduction in neurotransmitters, the death of tangle-bearing neurons and dementia (Scheme 1). Aggregation intermediates (often called oligomers) are now considered to be more toxic than amyloid plaques; and the production of reactive oxygen spe-

A mild entry to isoindolinones from furfural as renewable resource

A convenient transformation of furfural and derivatives into arene compounds is described. This process provides a straightforward access to isoindolinones from a renewable resource via the sequence of a tandem Ugi–Diels–Alder process followed by a ring-opening, dehydrating aromatisation. Five bonds are created and water is the sole by-product during this two-step sequence.

A Robust and Efficient Production and Purification Procedure of Recombinant Alzheimers Disease Methionine-Modified Amyloid-β Peptides.

An improved production and purification method for Alzheimer’s disease related methionine-modified amyloid-β 1–40 and 1–42 peptides is proposed, taking advantage of the formation of inclusion body in Escherichia coli. A Thioflavin-S assay was set-up to evaluate inclusion body formation during growth and optimize culture conditions for amyloid-β peptides production. A simple and fast purification protocol including first the isolation of the inclusion bodies and second, two cycles of high pH denaturation/ neutralization combined with an ultrafiltration step on 30-kDa cut-off membrane was established. Special attention was paid to purity monitoring based on a rational combination of UV spectrophotometry and SDS-PAGE analyses at the various stages of the process. It revealed that this chromatography-free protocol affords good yield of high quality peptides in term of purity. The resulting peptides were fully characterized and are appropriate models for highly reproducible in vitro aggregation studies.

Ethyl 2-[N-(tert-butyl-sulfin-yl)carbamo-yl]benzoate.

The title compound, C14H19NO4S, was obtained in quantitative yield by Lewis acid-catalysed alcoholysis of a phtalimide precursor. An intramolecular C—H⋯O hydrogen bond occurs. In the crystal, centrosymmetric dimers are formed by pairs of N—H⋯O hydrogen bonds between the sulfinyl O atoms and the carbamoyl N—H group of a neighboring molecule. C—H⋯O interactions feature in the crystal structure.

Expanding the Balz–Schiemann Reaction: Organotrifluoroborates Serve as Competent Sources of Fluoride Ion for Fluoro‐Dediazoniation

The Balz-Schiemann reaction endures as a method for the preparation of (hetero)aryl fluorides yet is eschewed due to the need for harsh conditions or high temperatures along with the need to isolate potentially explosive diazonium salts. In a departure from these conditions, we show that various organotrifluoroborates (RBF3 - s) may serve as fluoride ion sources for solution-phase fluoro-dediazoniation in organic solvents under mild conditions. This methodology was successfully extended to a one-pot process obviating aryl diazonium salt isolation. Sterically hindered (hetero)anilines are fluorinated under unprecedentedly mild conditions in good-to-excellent yields. Taken together, this work expands the repertoire of RBF3 - s to act as fluorine ion sources in an update to the classic Balz-Schiemann reaction.

Crystal structure of catena-poly[[[di­chlorido­copper(II)]-{μ-tert-butyl N-methyl-N-[4-(6-{[4-(pyridin-2-yl-κN)-1H-1,2,3-triazol-1-yl-κN3]meth­yl}-1,3-benzo­thia­zol-2-yl)phen­yl]carbamato}] aceto­nitrile monosolvate]

The title coordination polymer was obtained by combining an aqueous solution of copper(II) dichloride with the ligand {tert-butylmethyl[4-(6-{[4-(pyridin-2-yl-)1H-1,2,3-triazol-1-yl]methyl}-1,3-benzothiazol-2-yl)phenyl]carbamate in acetonitrile.

Expedited Route to Fully Substituted Amino-Pyrazole Building Blocks and Their Further Transformations

We report here an efficient and easily reproducible two-step approach to heterocycle-substituted amino-pyrazoles from heterocyclic acetonitriles and their unprecedented subsequent transformations to fully substituted pyrazoles. Such transformations include regioselective derivatization from polyamino derivatives, formation of tetracyclic compounds in up to 45% overall yield, and deaminative transformations through diazotization, followed by arylation through Suzuki–Miyaura cross-coupling and C–H activation, providing arylated pyrazoles in up to 71% yield over four steps. This strategy allows the swift introduction of significant molecular complexity to a range of scaffolds.