Synthesis of Sulfur-Containing Exo-Bicyclic Dienes and Their Diels-Alder Reactions To Access Thiacycle-Fused Polycyclic Systems.

The stereocontrolled synthesis of unprecedented sulfur-containing exo-bicyclic 1,3-dienes is reported through a palladium-catalyzed reductive cyclization of sulfur-linked 2-bromoenynes. The fused bicyclic structure provides a better stability to the thiacyclic diene compared to the simple 3,4-dimethylenetetrahydrothiophene. Their reactivity toward several dienophiles has been investigated, and various original thiacycle-fused polycyclic systems have been obtained with high or total diastereoselectivity.

MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor.

The Smoothened (Smo) receptor, a member of class F G protein-coupled receptors, is the main transducer of the Hedgehog (Hh) signaling pathway implicated in a wide range of developmental and adult processes. Smo is the target of anticancer drugs that bind to a long and narrow cavity in the 7-transmembrane (7TM) domain. X-ray structures of human Smo (hSmo) bound to several ligands have revealed 2 types of 7TM-directed antagonists: those binding mostly to extracellular loops (site 1, e.

Stereoselective multicomponent assembly of enantiopure oxazolopiperidines and -azepines.

A multicomponent reaction (MCR) based on a cyclohydrocarbonylation (CHC) driven by hydroformylation was set up toward the efficient diastereoselective preparation of oxazolopiperidines (4a-e) and -azepines (7a-d). The bicyclic oxazolidines were obtained from chiral N-alkenylamino alcohols via transient cyclic iminium intermediates that underwent an intramolecular cyclization from the appendant oxygen. On the basis of a series of different experimental conditions, the diastereocontrol observed during the formation of the oxazolidines is best explained by the stereoelectronic effect induced by an A(1,3)-strain in a common cyclic iminium intermediate (A).

Acylthiourea, acylurea, and acylguanidine derivatives with potent hedgehog inhibiting activity.

The Smoothened (Smo) receptor is the major transducer of the Hedgehog (Hh) signaling pathway. On the basis of the structure of the acylthiourea Smo antagonist (MRT-10), a number of different series of analogous compounds were prepared by ligand-based structural optimization. The acylthioureas, originally identified as actives, were converted into the corresponding acylureas or acylguanidines.

Identification and mechanism of action of the acylguanidine MRT-83, a novel potent Smoothened antagonist.

There is a clear need to develop novel pharmacological tools to improve our understanding of Smoothened (Smo) function in normal and pathological states. Here, we report the discovery, the mechanism of action, and the in vivo activity of N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (MRT-83), a novel potent antagonist of Smo that belongs to the acylguanidine family of molecules. MRT-83 fits to a proposed pharmacophoric model for Smo antagonists with three hydrogen bond acceptor groups and three hydrophobic regions.

Virtual screening-based discovery and mechanistic characterization of the acylthiourea MRT-10 family as smoothened antagonists.

The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions.

A general approach to aza-heterocycles by means of domino sequences driven by hydroformylation.

The development of hydroformylative domino reactions of easily accessible vinyl acetamides is described. Extremely regioselective hydroformylation of terminal double bounds provides a transient N-acyliminium that can be trapped by various nucleophiles to give several aza-heterocylic scaffolds in a diastereoselective manner.

Application of Rhodium-Catalyzed Cyclohydrocarbonylation to the Syntheses of Enantiopure Homokainoids.

Kainic acid, rigidified (S)-glutamic acid, is a well-known kainite receptor agonist for the excitatory transmission in the central nerve system. Our interest in highly selective kainite ligands, prompted us to design a series of new kainic homologues, "homokainoids", i.e.

Rhodium-catalyzed cyclohydrocarbonylation approach to the syntheses of enantiopure homokainoids.

Homologues of kainic acid, a naturally occurring potent glutamate receptor agonist, were designed based on a rigidified pipecolinoglutamic acid structure and can be regarded as homokainoids for their potential activities in the central nervous system. These novel homokainoids in an enantiomerically pure form were synthesized from enantiopure (R)- and (S)-Garner's aldehyde, featuring (i) the highly diastereoselective addition of alkenylcuprates to the acrylate intermediates and (ii) the Rh-catalyzed cyclohydrocarbonylation of homoallylic amine intermediates to construct the functionalized piperidine moiety in the key steps. For the introduction of a substituent at the 4- or 5-position of pipecolinoglutamic acid, a few different strategies were used, which successfully led to the formation of enantiopure homokainoids.

A new method for the synthesis of chiral beta-branched alpha-amino acids.

A new method for the synthesis of chiral beta-branched alpha-amino acids based on a copper-mediated directed allylic substitution reaction with Grignard reagents is reported. This is the first case in which a delta-stereogenic center is controlling the diastereoselectivity of an o-DPPB-directed allylic substitution. Depending on the alkene geometry of the starting material either diastereomer, anti or syn, is accessible with good levels of acyclic stereocontrol.

Identification and characterization of Hedgehog modulator properties after functional coupling of Smoothened to G15.

The seven-transmembrane receptor Smoothened (Smo) transduces the signal initiated by Hedgehog (Hh) morphogen binding to the receptor Patched (Ptc). We have reinvestigated the pharmacological properties of reference molecules acting on the Hh pathway using various Hh responses and a novel functional assay based on the coexpression of Smo with the alpha subunit of the G15 protein in HEK293 cells. The measurement of inositol phosphate (IP) accumulation shows that Smo has constitutive activity, a response blocked by Ptc which indicates a functional Hh receptor complex.

Microwaves make hydroformylation a rapid and easy process.

[reaction: see text] Hydroformylation of alkenes can be carried out in a few minutes under microwave activation at a relatively low pressure (40 psi) using commercially available catalysts and ligands. The 80 mL vial of a Discover microwave oven was connected to a cylinder of CO and H2, and after filling the reactor at 40 psi, a mixture of an alkene, the Wilkinson catalyst, and XANTPHOS was submitted to microwave irradiation giving, after 4 min, high conversion into the corresponding aldehyde without formation of the isomerized alkene.

Potentiation of apple procyanidin-triggered apoptosis by the polyamine oxidase inactivator MDL 72527 in human colon cancer-derived metastatic cells.

Apple procyanidins have chemopreventive properties in a model of colon cancer, they affect intracellular signalling pathways, and trigger apoptosis in a human adenocarcinoma-derived metastatic cell line (SW620). In the present study we investigated relationships between procyanidin-induced alterations in polyamine metabolism and apoptotic effects. Apple procyanidins diminish the activities of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, key enzymes of polyamine biosynthesis, and they induce spermidine/spermine N(1)-acetyltransferase, which initiates retroconversion of poly-amines.