Seto Group
Research Interests

 

 

Research program

Seto group members are working on various projects including high-throughput ee analysis of reaction products employing enzymes, asymmetric catalysis, synthesis and properties of protein tyrosine phosphatase inhibitors (PTPases) and cyclohexanone-based serine cysteine protease inhibitors. These projects are summarized below.

 

An Enzymatic Method to Determine Enantiomeric Excess: EMDee

M. Burak Onaran

This project describes a new high-throughput screening method for determining enantiomeric excess. This method, which we call EMDee, utilizes a lipase to process the allylic acetate products of an asymmetric reaction (Figure). The enzyme converts one of the product enantiomers to the corresponding alcohol. The rate of acetic acid that is produced during the reaction is proportional to the concentration of the enantiomer that is the substrate for the lipase. The protonation of a pH indicator by the acetic acid can be conveniently followed by observing a decrease in absorbance at 405 nm.
The Michaelis-Menten equation provides a direct relationship between the rate of this enzymatic acetate hydrolysis and the concentration of one of the allylic acetate enantiomers. Therefore, the rate of acetic acid production can be used as a direct measure of the enantiomeric excess of allylic acetate products that are obtained from asymmetric reactions. The method can measure the % ee of samples that range from 100% S to 100% R with an accuracy of approximately +/-10%. Furthermore, ~200 samples can be processed in one hour.

 

 

Asymmetric Catalysis

Chris Sprout, Meaghan Richmond

Our research project falls in the general category of asymmetric catalysis. We have been synthesizing amino acid based ligands in a modular fashion. The ligands are used in the dialkylzinc addition to aldehydes.We have found that Me2Zn, in the presence of our ligands, adds to 2-naphthaldehyde, 4-Cl-benzaldehyde, and benzaldehyde in 86%, 84%, and 81% enantiomeric excess (ee) respectively.
Inspiration for this project stems from the need for high-throughput screening methods to determine ee of large libraries of compounds. Combinatorial synthesis has aided pharmaceutical companies in the discovery of better drugs. We believe that utilization of parallel combinatorial libraries is the best way to find better catalysts. By designing a novel class of ligands with easily diversified subunits the power of combinatorial chemistry can be realized. The problem arises when one analyzes 1000+ products for ee by traditional chiral HPLC or GC. The answer involves a fast high-throughput screening methodology.
The ligands are designed to mimic the successful B-amino alcohols. The idea is to use an amide group which has a similar pka to an alcohol. We term these new ligands B-amino amides. The synthesis involves a simple HBTU coupling of a Boc-protected amino acid with a commercially available N,N-dialkylethylenediamine. Further diversification involves removal of the Boc
group and either capping with an acid chloride or a chloroformate. Other amino acids could also be added to build in more stereocenters into the ligands.

Sa Wang

My current work is focused on preparing a series of ligands for the enantioselective synthesis of secondary alcohols via catalytic addition of organozinc reagents to aldehydes. Since there are a variety of catalytic methods accessible for this transformation, we aim to get the simple and easy synthetic routes that could be realized in fast and practical process. By utilizing plenty of amino acid components, our interest is to get a class of modular amino-acid based catalytic ligands that allow easy incorporation of chirality.
Now I am working with Meaghan Richmond and Chris Sprout to try to realize a large assortment of these modified ligands. By beginning with amino acid as scaffold, an easy, two-step has been proposed and developed by introducing various functionalities, such as chiral alkyl side chains, diverse tertiary amines and carbamate moieties, at different points of the molecule. Finally, they are tested to have high ee(up to 99%) in the asymmetric addition of diethylzinc to aldehydes.

 

Synthesis and properties of protein tyrosine phosphatase inhibitors

Jian Xie, Antony Comeau

It’s well known that protein tyrosine phosphatases (PTPase) play very important roles in the cell activities. Opposing actions of PTPase and PTKase (protein tyrosine kinase) regulate the reversible tyrosine phosphorylation and dephosphorylation of proteins, which subsequently control the cell growth, mitogenesis, motility, cell-cell interaction, metabolism, gene transcription and the immune response, etc. Defective or inappropriate PTPase operation can result in wide spread diseases such as diabetes, cancers and immune dysfunctions. It has been found out that overexpressed PTPases such as PTP1B might induce Type II diabetes. Yersinia PTPase was found to be the important virulent determinant in the Black Death, or the Bubonic plague. Another interesting example is PTP1B-deficient mice showed increased insulin sensitivity and obesity resistance. All these studies suggest that inhibition against PTPases is an interesting drug target.
Our previous research found that a-ketoacid can work as the mimic of the phosphate. Recently it has been reported that there are two binding sites in the PTPase for substrate. This instantly suggests a method of improving the inhibitor binding affinity by incorporating two aryl a-ketoacid moieties into one single inhibitor structure. Jian Xie is working on library synthesis based on diamine backbone. Assay on crude inhibitors affords a relatively quick screening method.

Yen Ting Chen

Our research entails the study of a-keto carboxylic acids as inhibitors of protein tyrosine phosphatases (PTPases). PTPases are enzymes that catalyze the hydrolysis of phosphotyrosine residues and are one of the regulators of the signal transduction pathway. Several studies have found that overexpression of PTPases leads to several diseases such as obesity and type II diabetes. Recently, we have found that aryl a-ketoacids can function as inhibitors of the Yersinia PTPase, the causative agent of the bubonic plague. We are currently exploring the efficacy of a-ketoacids against other PTPases and the development of multivalent inhibitors designed to make contact with residues inside and around the enzyme active site.

 


Cyclohexanone-based serine cysteine protease inhibitors

Fengtian Xue

Cyclohexanone-based serine cysteine protease inhibitors have been developed by our group from late 90’s (1 is an example of this family of inhibitors). Our previous work about 4-heterocyclohexanone-based serine cysteine protease inhibitors indicates that through space electrostatic interaction can be used to predict the activity of inhibitors of papain, which prompts us to incorporate a sulfone group, a very good EWG in the 4-position of cyclohexanone ring to give 2, presumably, 2 should show better inhibition of the protease. Also, some other peptide and non-peptide hydrophobic functional group will be tried to replace the C-terminal Trp residue in 2. For long term goal, some dipeptides Gln or Thr at P3, and Lys or Arg at P4 will be appended to N-terminal of 2 to give 3, which will have better surface contact with the protease active site than 2, thus should show good specificity for protease.