ABSTRACT
A novel application of intramolecular base catalysis confers enhanced reaction rates for aminolysis ligations between peptide thioesters and peptides bearing N-terminal aspartate or glutamate residues. The broad scope of this process and its application in the total synthesis of the diabetes drug exenatide is demonstrated.
Subject(s)
Aspartic Acid/chemistry , Glutamic Acid/chemistry , Hypoglycemic Agents/chemical synthesis , Peptides/chemistry , Venoms/chemical synthesis , Catalysis , Esters/chemistry , Exenatide , Hypoglycemic Agents/chemistry , Molecular Structure , Peptides/chemical synthesis , Stereoisomerism , Sulfhydryl Compounds/chemistry , Venoms/chemistryABSTRACT
There is a paucity of chemical matter suitably poised for effective drug development. Improving the quality and efficiency of research early on in the drug discovery process has been a long standing objective for the drug industry and improvements to the accessibility and quality of compound screening decks might have a significant and positive impact. In the absence of specific molecular information that can be modeled and used predicatively we are far from identifying which small molecules are most relevant to emerging biological targets such as protein-protein interactions. Natural products have been historically successful as an entry point for drug discovery and recently screening libraries are being synthesized to emulate natural product like features.
Subject(s)
Biological Factors/chemistry , Biological Products/analysis , Combinatorial Chemistry Techniques/methods , Databases, Factual , Drug Evaluation, Preclinical/methods , Small Molecule Libraries , Drug Design , Humans , Molecular Structure , Quantitative Structure-Activity RelationshipABSTRACT
A novel ligation method for the synthesis of phosphopeptides and peptides is described, which utilises the inherent reactivity of a peptide bearing an N-terminal phosphoserine or phosphothreonine residue to facilitate amide bond formation with a range of C-terminal peptide thioesters.
Subject(s)
Peptides/chemistry , Phosphates/chemistry , Chromatography, High Pressure Liquid , Kinetics , Mass Spectrometry , Nuclear Magnetic Resonance, Biomolecular , Spectroscopy, Fourier Transform InfraredABSTRACT
The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Folic Acid Antagonists/chemical synthesis , Folic Acid Antagonists/pharmacology , Methicillin-Resistant Staphylococcus aureus/drug effects , Methicillin-Resistant Staphylococcus aureus/enzymology , Tetrahydrofolate Dehydrogenase/metabolism , Anti-Bacterial Agents/chemistry , Drug Evaluation, Preclinical , Folic Acid Antagonists/chemistry , Structure-Activity RelationshipABSTRACT
Through the synthesis of a focused library and SAR investigations, a more potent analogue of gemmacin (discovered in a previous diversity-oriented synthesis (DOS) campaign), gemmacin B, was discovered.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Sulfides/chemistry , Anti-Bacterial Agents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Microbial Sensitivity Tests , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Sulfides/pharmacologyABSTRACT
Diversity-oriented synthesis (DOS), which describes the synthesis of structurally diverse collections of small molecules, was developed, in part, to address combinatorial chemistry's shortfalls. In this paper, we hope to give an indication of what can be achieved using the DOS approach to library generation. We describe some of the most successful strategies utilized in DOS, with special focus on our own area of interest; DOS from simple, pluripotent starting materials.
Subject(s)
Chemistry, Organic/methods , Chemistry, Pharmaceutical/methods , Combinatorial Chemistry Techniques/methods , Pharmaceutical Preparations/chemical synthesis , Chemistry, Organic/trends , Chemistry, Pharmaceutical/trends , Combinatorial Chemistry Techniques/trends , Models, ChemicalABSTRACT
Diastereomeric 2-methoxycyclopentyl analogues of a natural quorum sensing signaling molecule from Pseudomonas aeruginosa were synthesized and screened in pigment production assays with P. aeruginosa and Serratia strain ATCC39006.
Subject(s)
Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , Quorum Sensing/drug effects , Binding Sites , Dose-Response Relationship, Drug , Hydrogen Bonding , Models, Molecular , Molecular Structure , Serratia/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The search for new molecular entities in drug discovery and chemical genetic programs requires the screening of high-quality collections of structurally diverse small molecules. The design and synthesis of such collections remains a major challenge to synthetic chemists. Recent strategies and results are presented in the context of the chemical space being interrogated.
Subject(s)
Combinatorial Chemistry Techniques/methods , Drug Design , Models, Chemical , Molecular StructureABSTRACT
Pseudomonas aeruginosa produces the quorum sensing signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). This natural product not only coordinates production of virulence factors by the bacterium, but also has immunomodulatory effects on the host organism. Immunomodulatory small molecules are valuable for immunology research and are potential therapeutics for autoimmune diseases such as rheumatoid arthritis, and immunosuppressive drugs following organ transplants. We describe the total synthesis of OdDHL using solid-supported reagents and scavengers, which has the potential to be used for automated analogue synthesis. OdDHL and four analogues were tested for their ability to activate or inhibit release of the pro-inflammatory mediators tumour necrosis factor alpha (TNFalpha) and nitric oxide (NO) from equine or murine macrophages (immune cells). Two of the analogues showed substantial immunomodulatory activity with these macrophages. One analogue showed differing species selectivity, being a potent antagonist in mouse cells, but a partial agonist in horse-derived macrophages. These compounds have the therapeutic potential to be used for protecting animals from bacterial septic shock.
Subject(s)
4-Butyrolactone/analogs & derivatives , Macrophages/drug effects , Macrophages/immunology , Molecular Probes/pharmacology , Pseudomonas aeruginosa/immunology , Pseudomonas aeruginosa/pathogenicity , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/chemistry , 4-Butyrolactone/pharmacology , Animals , Biological Assay , Cell Line , Horses , In Vitro Techniques , Mice , Molecular Probes/chemical synthesis , Molecular Probes/chemistry , Molecular Structure , Nitric Oxide/metabolism , Pigments, Biological/biosynthesis , Tumor Necrosis Factor-alpha/metabolism , Virulence/immunologyABSTRACT
Production of virulence factors and secondary metabolites is regulated in the phytopathogen Erwinia carotovora by quorum sensing involving N-acylated homoserine lactone (AHL) signaling molecules. Non-hydrolyzable AHL analogues were synthesized and screened in vivo. The biological activity of each compound was correlated with its ability to bind Erwinia AHL receptor proteins (LuxR homologues) in vitro. There is an excellent correlation between carbapenem production in vivo and in vitro binding to CarR. However, no such correlation could be found between exoprotease production and analogue binding to EccR. Our data are consistent with the involvement of a third, as yet uncharacterized LuxR homologue.
Subject(s)
4-Butyrolactone/analogs & derivatives , Pectobacterium carotovorum/chemistry , Repressor Proteins/metabolism , Signal Transduction , Trans-Activators/metabolism , 4-Butyrolactone/chemical synthesis , 4-Butyrolactone/pharmacology , Bacterial Proteins/biosynthesis , Binding Sites , Carbapenems/biosynthesis , Colony Count, Microbial , Exopeptidases/biosynthesis , Gene Expression Regulation/drug effects , Pectobacterium carotovorum/cytology , Pectobacterium carotovorum/metabolism , Structure-Activity RelationshipABSTRACT
Over the last decade or so, a wealth of research has established that bacteria communicate with one another using small molecules. These signals enable the individuals in a population to coordinate their behaviour. In the case of pathogens, this behaviour may include decisions such as when to attack a host organism or form a biofilm. Consequently, such signalling systems are excellent targets for the development of new antibacterial therapies. In this review, we assess how Gram-negative bacteria use small molecules for cell-cell communication, and discuss the main approaches that have been developed to interfere with it.
Subject(s)
Cell Communication/physiology , Gram-Negative Bacteria/physiology , Gram-Negative Bacteria/pathogenicity , VirulenceABSTRACT
The human pathogen Pseudomonas aeruginosa uses N-butyryl-L-homoserine lactone (BHL) and N-(3-oxododecanyl)-L-homoserine lactone (OdDHL) as small molecule intercellular signals in a phenomenon known as quorum sensing (QS). QS modulators are effective at attenuating P. aeruginosa virulence; therefore, they are a potential new class of antibacterial agent. The lactone in BHL and OdDHL is hydrolysed under physiological conditions. The hydrolysis proceeds at a rate faster than racemisation of the alpha-chiral centre. Non-hydrolysable, non-racemic analogues (small molecule probes) were designed and synthesised, replacing the lactone with a ketone. OdDHL analogues were found to be relatively unstable to decomposition unless they were difluorinated between the beta-keto amide. Stability studies on a non-hydrolysable, cyclohexanone analogue indicated that racemisation of the alpha-chiral centre was relatively slow. This analogue was assayed to show that the L-isomer is likely to be responsible for the QS autoinducing activity in P. aeruginosa and Serratia strain ATCC39006.
Subject(s)
Biochemistry/methods , Molecular Probes/chemistry , Pseudomonas aeruginosa/physiology , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/chemistry , 4-Butyrolactone/metabolism , Cyclohexanones/chemistry , Drug Evaluation, Preclinical/methods , Fluorine/chemistry , Homoserine/analogs & derivatives , Homoserine/chemistry , Hydrolysis , Isomerism , Ketones/chemistry , Molecular Probes/chemical synthesis , Molecular Probes/metabolism , Pseudomonas aeruginosa/pathogenicity , Serratia/physiology , Structure-Activity RelationshipABSTRACT
Bromopolystyrene beads with diameters of up to 600 microm have been derivatized completely, via bromine-magnesium exchange and interception with electrophiles, to yield high quality solid-supported reagents, scavengers and solid supports for use in diversity-oriented synthesis.
ABSTRACT
The crystal structures of anion complexes of two nitroaromatic functionalised isophthalamides are reported; the structures reveal assembly around anions in the solid-state and in the case of the fluoride complex of receptor 2, the formation of a double helix.