ABSTRACT
The tetrameric folding of ß-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for ß-tryptase.
Subject(s)
Protein Multimerization/drug effects , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Tryptases/antagonists & inhibitors , Binding SitesABSTRACT
Stochastic modeling of phylogenies raises five questions that have received varying levels of attention from quantitatively inclined biologists. 1) How large do we expect (from the model) the ratio of maximum historical diversity to current diversity to be? 2) From a correct phylogeny of the extant species of a clade, what can we deduce about past speciation and extinction rates? 3) What proportion of extant species are in fact descendants of still-extant ancestral species, and how does this compare with predictions of models? 4) When one moves from trees on species to trees on sets of species (whether traditional higher order taxa or clades within PhyloCode), does one expect trees to become more unbalanced as a purely logical consequence of tree structure, without signifying any real biological phenomenon? 5) How do we expect that fluctuation rates for counts of higher order taxa should compare with fluctuation rates for number of species? We present a mathematician's view based on an oversimplified modeling framework in which all these questions can be studied coherently.
Subject(s)
Models, Biological , Phylogeny , Stochastic Processes , Biodiversity , Biological Evolution , Extinction, BiologicalABSTRACT
Flash vacuum pyrrolysis of vinyl epoxides provides cis-dihydrofuran carboxylic esters in good yields and diastereoselectivities, which, on base-promoted epimerisation afford the complementary trans series. The compounds provide a viable template for a Lewis acid promoted cyclisation to provide the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane core found in the furofuran series of natural lignans. This strategy is stereodivergent and can be controlled to provide the exo-exo, exo-endo or endo-endo stereochemistries. The approach has been exemplified in syntheses of the sesamyl furofurans (+/-)-epiasarinin and (+/-)-asarinin.
Subject(s)
Furans/chemical synthesis , Cyclization , Furans/chemistry , Mass SpectrometryABSTRACT
A new generation of PNP compounds bearing different diarylphosphine groups were prepared and used as ligands in palladium-catalysed Suzuki cross-coupling reactions. Rates of oxidative addition of iodobenzene to (PNP)Pd[0] complexes were measured using UV spectroscopy. Synergistic effects between the N- and P- substituents were identified and correlated in redox and catalytic chemistry.
ABSTRACT
A strategy for the stereoselective synthesis of all the possible diastereoisomers of the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane (furofuran) lignans from a single dihydrofuran precursor is described. The key steps involve a diastereocontrolled templated cationic cyclization followed by stereoselective reduction of the resulting methyl glycoside.
ABSTRACT
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.
Subject(s)
Adjuvants, Immunologic/chemistry , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/immunology , Animals , Binding Sites , Cell Division/drug effects , Drug Design , Edema/drug therapy , Enzyme Inhibitors/chemistry , Indoles/chemistry , Inhibitory Concentration 50 , Interleukin-2/pharmacology , Janus Kinase 3 , Mice , Oxyquinoline/chemistry , Phosphorylation/drug effects , Protein Binding , Protein Structure, Tertiary , Protein-Tyrosine Kinases/metabolism , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Precursors/antagonists & inhibitors , Indoles/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Basophils/drug effects , Cell Degranulation/drug effects , Cell Line , Enzyme Inhibitors/pharmacology , Humans , Indoles/chemistry , Inhibitory Concentration 50 , Intracellular Signaling Peptides and Proteins , Oxyquinoline/chemistry , Oxyquinoline/pharmacology , Phosphorylation/drug effects , Rats , Solubility , Structure-Activity Relationship , Syk KinaseABSTRACT
[reaction: see text] Epiasarinin, an endo-endo furofuran, has been synthesized from piperonal via a five-step route with good stereocontrol. The sequence involves Darzens condensation, alkenyl epoxide-dihydrofuran rearrangement, and a Lewis acid mediated cyclization.
