Christopher T. Seto

Enantioselective synthesis of 1-aryltetrahydroisoquinolines.

1-Aryltetrahydroisoquinolines (1-arylTHIQs) are important structural motifs in many alkaloids and biologically active compounds. Ligand 2a promotes the enantioselective addition of arylzinc reagents to 3,4-dihydroisoquinoline N-oxide to yield (S)-1-arylTHIQs in 97-99% ee. Pinacol arylboronic esters are the optimal precursors for the arylzinc reagents. This method is applied to the enantioselective synthesis of Solifenacin.

Biotinylation of substituted cysteines in the nicotinic acetylcholine receptor reveals distinct binding modes for alpha-bungarotoxin and erabutoxin a.

Although previous results indicate that α-subunit residues Trp187, Val188, Phe189, Tyr190, and Pro194 of the mouse nicotinic acetylcholine receptor are solvent-accessible and are in a position to contribute to the α-bungarotoxin (α-Bgtx) binding site (Spura, A., Russin, T. S., Freedman, N. D., Grant, M., McLaughlin, J. T., and Hawrot, E. (1999) Biochemistry38, 4912–4921), little is known about the accessibility of other residues within this region. By determining second-order rate constants for the reaction of cysteine mutants at α184–α197 with the thiol-specific biotin derivative (+)-biotinyl-3-maleimidopropionamidyl-3,6-dioxaoctanediamine, we now show that only very subtle differences in reactivity (∼10-fold) are detectable, arguing that the entire region is solvent-exposed. Importantly, biotinylation in the presence of saturating concentrations of the long neurotoxin α-Bgtx is significantly retarded for positions αW187C, αF189C, and reduced wild-type receptors (αCys192 and αCys193), further emphasizing their major contribution to the α-Bgtx binding site. Interestingly, although biotinylation of position αV188C is not affected by the presence of α-Bgtx, erabutoxin a, which is a member of the short neurotoxin family, inhibits biotinylation at position αV188C, but not at αW187C or αF189C. Taken together, these results indicate that short and long neurotoxins establish interactions with distinct amino acids on the nicotinic acetylcholine receptor.

Design and synthesis of hydrogen-bonded aggregates. Theory and computation applied to three systems based on the cyanuric acid-melamine lattice☆

Abstract The rational design of complex, self-assembling, non-covalent aggregates requires a workable understanding of association phenomena, a reliable rule-based mechanism to predict and compare the stabilities of potential target structures, and straightforward synthetic routes to the molecular components of the aggregates. Systems based on the cyanuric acid-melamine lattice satisfy many of these criteria. This paper reviews the design, synthesis, and characterization of three related aggregates, and summarizes initial results of two models: i) a computational model that predicts relative stabilities of aggregates; and ii) a theoretical model that assesses relative entropies of aggregation.

A focused library of protein tyrosine phosphatase inhibitors.

Protein tyrosine phosphatases such as PTP1B and YopH are potential targets for the development of therapeutic agents against a variety of pathological conditions including diabetes, obesity, and infection by the bacterium Yersinia pestis. A focused library of bidentate α-ketoacid-based inhibitors has been screened against several tyrosine phosphatases. Compound 2a has IC(50) values of 43 and 220 nM against YopH and PTP1B, respectively, and shows a 30-fold selectivity for PTP1B over the closely related phosphatase TCPTP.

Hydrolysis of Amides Catalyzed by 4-Heterocyclohexanones: Small Molecule Mimics of Serine Proteases

The base-promoted hydrolysis of amide substrates that contain a thiol substituent in the position α to the amide carbonyl group is effectively catalyzed by 4-heterocyclohexanones [Eq. (1)]. The proposed mechanism of the hydrolysis reaction mimics that employed by serine proteases, and involves equilibrium binding of the substrate to the catalyst, formation of an acyl-catalyst intermediate, and deacylation of the intermediate to release the product and regenerate the catalyst.

AgPd Nanoparticles Deposited on WO2.72 Nanorods as an Efficient Catalyst for One-Pot Conversion of Nitrophenol/Nitroacetophenone into Benzoxazole/Quinazoline

We report a seed-mediated growth of 2.3 nm AgPd nanoparticles (NPs) in the presence of 40 × 5 nm WO2.72 nanorods (NRs) for the synthesis of AgPd/WO2.72 composites. The strong interactions between AgPd NPs and WO2.72 NRs make the composites, especially the Ag48Pd52/WO2.72, catalytically active for dehydrogenation of formic acid (TOF = 1718 h-1 and Ea = 31 kJ/mol) and one-pot reactions of formic acid, 2-nitrophenol, and aldehydes into benzoxazoles in near quantitative yields under mild conditions. The catalysis can also be extended to the one-pot reactions of ammonium formate, 2-nitroacetophenone, and aldehyde for high yield syntheses of quinazolines. Our studies demonstrate a new catalyst design to achieve a green chemistry approach to one-pot reactions for the syntheses of benzoxazoles and quinazolines.

Fluorogenic Peptide Substrates for Serine and Threonine Phosphatases

A new fluorescent assay for Ser/Thr protein phosphatases has been developed. Hydrolysis of a phosphoSer residue liberates the Ser hydroxyl group, which induces a cyclization reaction on the N-terminal carbamate and releases a fluorescent reporter. Sequence selectivity is observed using several peptide substrates against alkaline phosphatase (ALP), bacteriophage lambda protein phosphatase (lambda-PPase), and vaccinia H1 related phosphatase (VHR). These studies suggest that the assay could be a useful tool for profiling the substrate specificities of medicinally important phosphatases.

Synthesis of cyclohexanone-based cathepsin B inhibitors that interact with both the S and S′ binding sites

Abstract Solution and solid phase methods are described for the synthesis of inhibitors of the cysteine protease cathepsin B. These inhibitors are based on a cyclohexanone pharmacophore and are designed to interact with both the S and S′ subsites of the enzyme active site.

Maximizing the Catalytic Activity of Nanoparticles through Monolayer Assembly on Nitrogen-Doped Graphene

We report a facile method for assembly of a monolayer array of nitrogen-doped graphene (NG) and nanoparticles (NPs) and the subsequent transfer of two layers onto a solid substrate (S). Using 3 nm NiPd NPs as an example, we demonstrate that NiPd-NG-Si (Si=silicon wafer) can function as a catalyst and show maximum NiPd catalysis for the hydrolysis of ammonia borane (H3 NBH3 , AB) with a turnover frequency (TOF) of 4896.8 h-1 and an activation energy (Ea ) of 18.8 kJ mol-1 . The NiPd-NG-S catalyst is also highly active for catalyzing the transfer hydrogenation from AB to nitro compounds, leading to the green synthesis of quinazolines in water. Our assembly method can be extended to other graphene and NP catalyst materials, providing a new 2D NP catalyst platform for catalyzing multiple reactions in one pot with maximum efficiency.

Macrocyclic inhibitors for the serine protease plasmin

Macrocyclic inhibitors for the serine protease plasmin were synthesized and evaluated. The inhibitors were constructed starting from a cyclohexanone core. This core was linked to either the C- or N-terminus of a peptide so that the inhibitors were designed to interact with the non-primed or primed binding sites of the protease. Macrocycles were prepared by connecting the side chain of Tyr or Trp, via a short linker, to one end of the peptide. The activities of the macrocyclic inhibitors, while modest, were up to 10-fold more potent than a related non-cyclic analog.