Tetrahydropyridine LIMK inhibitors: Structure activity studies and biological characterization.

LIM Kinases, LIMK1 and LIMK2, have become promising targets for the development of inhibitors with potential application for the treatment of several major diseases. LIMKs play crucial roles in cytoskeleton remodeling as downstream effectors of small G proteins of the Rho-GTPase family, and as major regulators of cofilin, an actin depolymerizing factor. In this article we describe the conception, synthesis, and biological evaluation of novel tetrahydropyridine pyrrolopyrimidine LIMK inhibitors.

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo.

LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades.

Probe drug T-1032 N-oxygenation mediated by cytochrome P450 3A5 in human hepatocytes in vitro and in humanized-liver mice in vivo.

Polymorphic cytochrome P450 3A5 (CYP3A5) expression contributes to individual differences in the pharmacokinetics of probe drugs. The identification of suitable in vivo CYP3A5 probes would benefit drug metabolism and drug interaction studies using chimeric mice with humanized liver. In this study, we investigated the pharmacokinetic profiles of T-1032, which is known as an in vitro CYP3A5 probe substrate, using humanized-liver mice.

Gold(I)-Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Alkynes: Access to Original Heterospirocycles.

We report here a simple and robust gold-catalyzed annulation reaction, giving - and -spirocycles in good to excellent yields. We have prepared a library of protected amines and tertiary alcohols that give, upon cyclization with alkynes, a representative set of heterospirocycles and illustrate reaction compatibility with diverse functional groups. A change in catalytic activity is possible by modifying the solvent, and two original tricyclic spirocycles were synthesized in a tandem reaction.

Perinatal Exposure to the Cyanotoxin β-N-Méthylamino-L-Alanine (BMAA) Results in Long-Lasting Behavioral Changes in Offspring-Potential Involvement of DNA Damage and Oxidative Stress.

We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD-like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim, female mice were intranasally exposed to low doses of BMAA, 50 mg kg three times a week from embryonic days 7-10 to postnatal day 21.

Controlled Dimroth Rearrangement in the Suzuki-Miyaura Cross Coupling of Triazolopyridopyrimidines.

Polynitrogen heterocycles are often subject to Dimroth rearrangement which consists of ring opening, bond rotation, and ring closure. In this note, we report a synthesis of two new families of triazolopyridopyrimidines. Successful functionalization via a Suzuki-Miyaura coupling was performed with total control of triazole (Dimroth) isomerization based on the judicious choice of reaction conditions.

30ièmes Journées Franco-Belges de Pharmacochimie.

The "Journées Franco-Belges de Pharmacochimie" is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.

The azaindole framework in the design of kinase inhibitors.

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed.

A further contribution to the study of sagittamide A: synthesis of a pivotal intermediate belonging to a rare L-series.

A key saggitamide intermediate corresponding to a rare sugar framework has been obtained. This approach should help to establish the overall configuration of more complex structures of the sagittamide family.

Proposal of a set of model polymer additives designed for confocal FRAP diffusion experiments.

The migration of additives from food packaging to food stuffs is kinetically governed by the diffusion coefficient (D) of the additive within the polymer. Food safety authorities have recently allowed the use of mathematical models to predict D, with the additive molecular weight as a single entry parameter. Such models require experimental values to feed the databases, but these values are often scattered.

Directed diastereoselectivity in the asymmetric claisen/metathesis reaction sequence.

The Claisen/metathesis sequence is a versatile synthetic tool for the synthesis of quaternary hydroxy and amino acid carbocycles. By correctly choosing both the configuration of the allylic alcohol and the double bond geometry, specific access to any one of four possible stereoisomers is possible in good yield and excellent diastereoselectivity. The enantiomerically pure allylic alcohols are easily obtained by addition of terminal alkynes to aldehydes.

Preparative isolation of huperzines A and B from Huperzia serrata by displacement centrifugal partition chromatography.

The pH-zone refining centrifugal partition chromatography technique was used to separate the two acetylcholinesterase inhibitors huperzines A and B from a crude alkaloid extract of the club moss Huperzia serrata. Complete co-elution of huperzines A and B was initially observed with the well-known methyl tert-butyl ether-acetonitrile-water (4:1:5, v/v/v) solvent system with triethylamine (8mM) as the displacer and methane sulfonic acid (6mM) as the retainer. An efficient biphasic system was designed on the basis of solvent association that provided selectivity in the elution mode: n-heptane/ethyl acetate/n-propanol/water (5:15:35:45, v/v/v/v).

Structure-activity relationships of some hederagenin diglycosides: haemolysis, cytotoxicity and apoptosis induction.

Hederagenin saponins are largely represented in nature and possess many biological activities such as haemolytic, antiviral, fungicidal, molluscicidal or cytotoxic, partially due to their interaction with the cell membrane. The lysis of erythrocytes (haemolysis) is a simple test to evaluate this adsorption, and this activity has been linked to the structure of the aglycone and also depends on the sugar moiety of the saponin. To further complete our study of the structure-activity relationships of triterpenoid saponins, alpha-hederin and related hederagenin diglycosides were synthesized to better understand the influence of the second sugar (alpha-L-rhamnose, beta-D-xylose or beta-D-glucose) and the substitution of this sugar on alpha-L-arabinose (position 2, 3 or 4).

Selective synthesis of alpha-C-(alkynyl)-galactosides by an efficient tandem reaction.

Several alpha-C-(alkynyl)-galactosides were synthesized using a tandem reaction involving the addition of a metal alkynylide to a chiral acyclic epoxyaldehyde, followed by an in situ closure of the generated alkoxide on the epoxide function.

Synthesis and hemolytic activity of some hederagenin diglycosides.

Glycosylation of hederagenin with the trichloroacetimidate derivatives of six commercial disaccharides (D-cellobiose, D-lactose, D-maltose, D-melibiose, D-gentiobiose, D-isomaltose) was performed giving the protected saponins in high yields. Deprotection then gave the saponins which were transformed into the corresponding methyl esters. The hemolytic activity of these synthetic hederagenin diglycosides was measured in order to establish structure-activity relationships based on the type and sequence of the attached sugar for the free carboxylic acid and methyl ester saponins.

Synthesis of the trisaccharide portion of soyasaponin beta g: evaluation of a new glucuronic acid acceptor.

The synthesis of the trisaccharide portion of soyasaponin beta g was successfully achieved using a new glucuronic acid acceptor: methyl 1-O-allyl-3,4-di-O-methoxymethyl-beta-D-glucuronate (9). This compound and methyl 1-O-allyl-3,4-di-O-tert-butyldimethylsilyl-beta-D-glucuronate (8) were both prepared from glucuronolactone via a glycal intermediate. The former compound 9 was successfully coupled to ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-beta-D-galactopyranoside (13) in excellent yield.