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
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.
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.
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.
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 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.