The Lipton Group

Purdue University 

Current Research Projects

 


Design and Synthesis of Biologically Active Molecules

Research1

Novel Antimicrobial Compounds: Inhibitors for Class II HMG-CoA Reductase

In 2014, the Infections Diseases Society of America (IDSA) declared multiple drug resistant bacteria to be a “substantial threat to US public health and national security”. 

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is an enzyme that is present in both eukaryotic(I-HMGR) and prokaryotic (II-HMGR) species.  It is responsible for catalyzing the reduction of HMG-CoA to mevalonate through a 4 electron oxidoreduction. In prokaryotes, mevalonate is a precursor to isopentenyl disphosphate (IPP), which is a component of undecaprenol, a lipid carrier.  Undecaprenol is required for bacterial cell wall synthesis.  The active site of II-HMGR consists of several different key residues compared to eukaryotic I-HMGR, making it feasible to design a molecule to selectively inhibit one in the presence of the other.

This project is currently focused on designing optimized inhibitors for II-HMGR, as well as identification of a unknown secondary target.  

U.S. Patent 9,604,925, 2017



Development of Novel Synthetic Methodology

Photo-cleavable BAL Linker for Solid-Phase Peptide Synthesis

Solid-phase peptide synthesis (SPPS) is a commonly used, iterative method of building peptides that are linked at one end to an insoluble solid support.  Various protecting group strategies have been used to differentiate between side chain, N-, and C-terminus functionalities.  Most of these protecting groups are either acid- or base-labile, thus limiting the combintations that can be used. 

The peptide is attached to the solid-support through a 'linker', an organic molecule that can be cleaved in the final step under varying conditions to release the completed peptide.  Backbone Amide Linkers (BALs) are commonly used as a solid-support anchor to make cyclic peptides or other C-terminal modifications.  However, many of these Linkers release the peptide under the same acidic conditions used for deprotection of many side chains. 

Work in our group is currently focused on developing an acid-stable, photolabile linker that is cleaved upon exposure to 365nm wavelength light.
        

1,1-Dimethyl Ester Protecting Group for C-terminal Modifications in Solid-Phase Peptide Synthesis

In the BAL strategy, the C-terminus is free and thus two semi-permanent protecting groups, one for each terminus, are required.  These two groups must be orthogonal with eachother, with the peptide-BAL linkage and the side-chain protecting groups.

Palladium-labile C-terminal allyl protection is required during an Fmoc-based BAL synthesis for this reason. However, allyl protection results in near-quantitative formation of diketopiperazine (DKP) upon Fmoc cleavage at the dipeptide stage. Steric bulk reduces this side reaction, but such C-terminal protecting groups (e.g. t-bu ester) are problematic as the peptide is cleaved from the linker under the highly acidic conditions needed to deprotect the ester.  

Our lab has focused on a method to remedy this issue by developing a palladium(0)-labile C-terminal protecting group which also reduces DKP formation through steric bulk.   

J. Org. Chem.201883 (15), pp 7762–7770