Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified.

Discovery of 2-amino-6-carboxamidobenzothiazoles as potent Lck inhibitors.

A novel series of 2-amino-6-carboxamidobenzothiazole was discovered to have potent Lck inhibitory properties. A highly efficient chemistry was developed. Also described are the detailed SAR study and the BaF3 cell line profiling for this series.

Au(I)-catalyzed annulation of enantioenriched allenes in the enantioselective total synthesis of (-)-rhazinilam.

Highly stereoselective Au(I)-catalyzed pyrrole additions to enantioenriched allenes afford a unique entry to optically active heterocycles. Asymmetric quaternary carbons can be installed with concurrent heterocycle annulation utilizing this methodology. The enantioenriched allenes are conveniently obtained by catalytic asymmetric acyl halide-aldehyde cyclocondensations and SN2' ring opening of the resulting enantioenriched beta-lactones.

Design and synthesis of simple macrocycles active against vancomycin-resistant enterococci (VRE).

16-membered meta,para-cyclophanes mimicking the vancomycin binding pocket (D-O-E ring) were designed and synthesized. The structural key features of these biaryl ether containing macrocycles are (1) the presence of beta-amino-alpha-hydroxy acid or alpha,beta-diamino acid as the C-terminal component of the cyclopeptide and (2) the presence of a hydrophobic chain or lipidated aminoglucose at the appropriate position. Cycloetherification by an intramolecular nucleophilic aromatic substitution reaction (S(N)Ar) is used as the key step for the construction of the macrocycle.

Competitive stereochemical control operative during conrotatory electrocyclization of helically equilibrating diquinanyl-substituted 1,3,5,7-octatetraenyl bisenolates.

[Carbohydrate structure: see text] Activation of the squarate ester cascade by adding the lithiated bicyclo[3.3.0]octene 20 and vinyllithium sequentially to 1 results in the isolation of the four tetracyclic products 21-24.

Identification of synthetic compounds active against VRE: the role of the lipidated aminoglucose and the structure of glycopeptide binding pocket.

A modified vancomycin binding pocket (D-O-E ring) incorporating an alpha-hydroxy-beta-amino acid at the AA4 position is designed and synthesized. Some of these compounds display potent bioactivities against both sensitive- and resistant-strains (8 microg/ml against VREF). Both the lipidated aminoglucose and the structure of the 16-membered macrocycle are found to be important for the anti-VRE activities.

Synthesis of beta-amino-alpha-hydroxy esters and beta-amino-alpha-azido ester by Sharpless asymmetric aminohydroxylation, byproducts analysis.

[reaction: see text] Synthesis of enantiomerically pure beta-amino-alpha-hydroxy esters (1, 2) and beta-amino-alpha-azido ester (3) using Sharpless AA as a key step is described. A hitherto unreported side reaction, the oxidation of the beta-hydroxy-alpha-amino ester (5) into the alpha,alpha-di-tert-butyloxycarbamoyl-beta-ketoester (8) under AA conditions, is documented.

Design and synthesis of macrocycles active against vancomycin-resistant enterococci (VRE): the interplay between d-Ala-d-Lac binding and hydrophobic effect.

A modified vancomycin binding pocket (D-O-E ring) incorporating a CHNHCOR function at the AA4 position is designed and synthesized. Potent bioactivities against both sensitive- and resistant-strain are found for some of these compounds (MIC 4 microg/mL against VREF). From this preliminary SAR studies, it was speculated that the D-Ala-D-Ala binding was required for this series of compounds since the corresponding des-leucine derivative is inactive.

Exploratory studies aimed at a synthesis of vinigrol. 4. Probe of possible means for direct connection of the side arms and of ring-contraction alternatives.

Attempts have been made to gain access to the vinigrol structural framework by way of three routes. These include reductive transannular cyclization, adaptation of the Ramberg-Backlund rearrangement, and deployment of the lactam-sulfoxide ring contraction protocol. While the first of these options involves direct transannular C-C bond formation, the other two embody the concept of larger ring construction as a prelude to ring contraction.

Exploratory studies aimed at a synthesis of vinigrol. 2. Attempts to exploit ring-closing metathesis for construction of the central cyclooctane belt.

A program directed to the possible adaptation of ring closing metathesis to a total synthesis of vinigrol is described. With a convenient route to intermediates of general type 3 available from a prior investigation, several candidate substrates were prepared. These included the epoxy dienes 10 and 22, the diacetoxy triene 42, and the heavily functionalized cyclohexane 48.

Synthetic studies aimed at (-)-cochleamycin A. Evaluation of late-stage macrocyclization alternatives.

An efficient route to the fully functionalized ABC ring systems of the unnatural enantiomer of cochleamycin A was developed. L-(-)-Malic and L-(-)-ascorbic acids served well as starting materials for the two building blocks used to construct an (E,Z,E)-1,6,8-nonatriene intermediate. The AB part structure was assembled by way of a stereocontrolled intramolecular Diels-Alder cycloaddition via adoption of an endo transition state.