ABSTRACT
With the apparition of concepts such as allosteric modulation and functional selectivity the field of G-protein coupled receptors drug discovery has regained its momentum. To better address this paradigm shift new screening technologies were developed. To identify novel GPCR ligands the screening method of choice was based upon functional assay for the last decade and is now being complemented by several innovative binding technologies. An overview of these assays, as well as an example of a fully integrated platform aiming at identifying novel allosteric modulator with the appropriate profile are presented in this review.
Subject(s)
Receptors, G-Protein-Coupled/metabolism , Allosteric Regulation/drug effects , Animals , Binding Sites/drug effects , Drug Discovery , HumansABSTRACT
A novel indolizine class of compounds was identified as TRPV1 antagonist from an HTS campaign. However, this indolizine class proved to be unstable and reacted readily with glutathione when exposed to light and oxygen. Reactivity was reduced by the introduction of a nitrogen atom alpha to the indolizine nitrogen. The pyrrolopyridazine core obtained proved to be inert to the action of light and oxygen. The synthesis route followed the one used for the indolizine compounds, and the potency and ADMET profile proved to be similar.
Subject(s)
Pyridazines/chemistry , Pyrroles/chemistry , TRPV Cation Channels/antagonists & inhibitors , Animals , Caco-2 Cells , Cell Membrane Permeability/drug effects , Drug Evaluation, Preclinical , Humans , Indolizidines/chemistry , Microsomes, Liver/metabolism , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
The diarylquinoline R207910 (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. Though R207910-resistant mycobacteria bear mutations in ATP synthase, the compound's precise target is not known. Here we establish by genetic, biochemical and binding assays that the oligomeric subunit c (AtpE) of ATP synthase is the target of R207910. Thus targeting energy metabolism is a new, promising approach for antibacterial drug discovery.
Subject(s)
ATP Synthetase Complexes/metabolism , Antitubercular Agents/pharmacology , Quinolines/pharmacology , ATP Synthetase Complexes/chemistry , ATP Synthetase Complexes/drug effects , Bacterial Proteins/chemistry , Bacterial Proteins/drug effects , Bacterial Proteins/metabolism , Bacterial Proton-Translocating ATPases , Binding Sites , Diarylquinolines , Electrophoresis, Gel, Two-Dimensional , Kinetics , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/enzymology , Protein Subunits/drug effects , Protein Subunits/isolation & purification , Protein Subunits/metabolismABSTRACT
The proposed short synthesis involves two key steps: Oxidation of the isopropylidene derivative of the 3-fluoronucleoside possessing a free hydroxyl group in 2-position and acetylation of deprotected 3-fluoro-2-ketonucleoside which, after a beta-elimination reaction, gives the desired unsaturated ketonucleoside 5.
Subject(s)
Fluorine/chemistry , Fluorouracil/analogs & derivatives , Ketones/chemistry , Nucleosides/chemistry , Uracil/analogs & derivatives , Chromatography, Thin Layer , Fluorouracil/chemical synthesis , Fluorouracil/pharmacology , Immunosuppressive Agents/pharmacology , Magnetic Resonance Spectroscopy , Models, Chemical , Nucleosides/chemical synthesis , Uracil/chemical synthesisABSTRACT
[reaction: see text] A short and convenient diastereoselective synthesis of all-carbon spirocylic molecules was developed. A straightforward protocol that involves rearrangement of the diene-Fe(CO)(3) complex followed by cyclization delivers the desired product. The reaction substrates were easily prepared by reaction of an appropriate nucleophile and a cyclohexadienyl-Fe(CO)(3) cation.
Subject(s)
Alkenes/chemistry , Iron/chemistry , Spiro Compounds/chemical synthesis , Catalysis , Cyclization , Diterpenes/chemistry , Polycyclic Sesquiterpenes , Stereoisomerism , Terpenes/chemistryABSTRACT
The palladium-catalyzed carbocyclization of allene-diene derivatives leading to the stereospecific formation of various 4-substituted [4.3.0] and [5.3.0] bicyclic systems is presented. Different functionalities were introduced at the C-4 position of the bicyclic systems by using a range of external nucleophiles such as carboxylic acids, alcohols, phenols, and thiophenols. In the previous protocol acetic acid was used as solvent and also served as nucleophile. In this new methodology, reactions were run in nonnucleophlic solvents such as CH(2)Cl(2) or acetone in the presence of the appropriate nucleophile, making this new protocol a more versatile tool in organic synthesis. It is noteworthy that the Pd(II)-catalyzed cyclization of cycloheptadiene-derivative 1b gave exclusively the trans-annulated bicycle 4. Depending on the nature of the nucleophile, the regioselectivity of the reaction could be tuned to afford exclusively 4b or 4c' (Scheme 1). The mechanistic pathway is discussed.
ABSTRACT
Reaction of allene-substituted cyclohexa- and cyclohepta-1,3-dienes with [PdCl(2)(PhCN)(2)] gave eta(3)-(1,2,3)-cyclohexenyl- and eta(3)-(1,2,3)-cycloheptenylpalladium complexes, respectively, in which C-C bond formation between the allene and the 1,3-diene has occurred. Analysis of the (pi-allyl)palladium complexes by NMR spectroscopy, using reporter ligands, shows that the C-C bond formation has occurred by a trans carbopalladation involving nucleophilic attack by the middle carbon atom of the allene on a (pi-diene)palladium(II) complex. The stereochemistry of the (pi-allyl)palladium complexes was confirmed by benzoquinone-induced stereoselective transformations to allylic acetates.
ABSTRACT
In the palladium-catalyzed cyclization of allenic allylic esters using Pd(dba)2 as catalyst, it was shown that the allene acts as a carbon nucleophile. Intermediates were isolated and stereochemical studies established that the double bond of the allene has attacked the (pi-allyl)palladium intermediate on the face opposite to that of palladium.