Kinetics and mechanism of organocatalytic aza-Michael additions: direct observation of enamine intermediates.

The imidazoles 1a–g add to the CC-double bond of the iminium ion 2 with rate constants as predicted by the equation log k = sN(N + E). Unfavourable proton shifts from the imidazolium unit to the enamine fragment in the adduct 3 account for the failure of imidazoles to take part in iminium-activated aza-Michael additions to enals

Counterion effects in iminium-activated electrophilic aromatic substitutions of pyrroles.

Electrophilic substitution of pyrroles by a,b-unsaturated iminium ions is slow in acetonitrile when only weakly basic counterions are present. When the reactions are carried out in the presence of KCF3CO2, fast deprotonation of the intermediate r-adducts occurs, and the rate constant for the rate-determining CC bond-forming step can be predicted from the electrophilicity parameter E of the iminium ion and the N and s parameters of the pyrroles

Light-Driven Enantioselective Organocatalytic β-Benzylation of Enals

Altres ajuts: Programa CERCA (Generalitat de Catalunya)A photochemical organocatalytic strategy for the direct enantioselective β-benzylation of α,β-unsaturated aldehydes is reported. The chemistry capitalizes upon the light-triggered enolization of 2-alkyl-benzophenones to afford hydroxy- o -quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael-type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring-opening

Synthesis and in vitro and in vivo characterization of highly β1-Selective β-Adrenoceptor partial agonists

β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1- selectivity

Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors

EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harboring activating mutations in the EGFR kinase1,2, but resistance arises rapidly, most frequently due to the secondary T790M mutation within the ATP-site of the receptor.3,4 Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant5,6, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond7. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternate mechanisms of action. Here we describe rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild type receptor. A crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays, but as a single agent is not effective in blocking EGFR-driven proliferation in cells due to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state8. We observe dramatic synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization9,10, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by L858R/T790M EGFR and by L858R/T790M/C797S EGFR, a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors