The p110 delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors.

Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies

Catalytic Asymmetric C−H Activation of Silyl Enol Ethers as an Equivalent of an Asymmetric Michael Reaction

Catalytic Asymmetric C−H Activation of Silyl Enol Ethers as an Equivalent of an Asymmetric Michael Reactio

Catalytic Asymmetric Allylic C−H Activation as a Surrogate of the Asymmetric Claisen Rearrangement

Tetrakis[N-[4-dodecylphenyl)sulfonyl]-(S)-prolinato]-dirhodium [Rh2(S-DOSP)4] catalyzed decomposition of methyl aryldiazoacetates in the presence of alkenes results in allylic C−H activation by means of a rhodium-carbene induced C−H insertion. The resulting γ,δ-unsaturated esters are equivalent to products that would be traditionally obtained from an asymmetric Claisen rearrangement. Highly regio- and enantioselective C−H insertions can be achieved, and in certain cases, good diastereocontrol is also possible