Biomimetic catalytic transformation of toxic a-oxoaldehydes to high-value chiral a-hydroxythioesters using artificial glyoxalase I

Through millions of years of evolution, Nature has accomplished the development of the ideal catalysts called enzymes that catalyze the biological chemical reactions necessary to sustain all life on Earth. Thus, lessons from how natural enzymatic systems operate can therefore be very important for the design of the more efficient and environmentally beneign catalytic systems.

Glyoxalases (I and II) and glutathione constitute a set of glyoxalase enzymes, which carry out the detoxification of methylglyoxal and other reactive a-keto aldehydes by the sequential action of two thiol-dependent enzymes. First, transition metal containing glyoxalase I catalyses the formation and isomerization of the hemithioacetal, which was formed spontaneously between glutathione (GSH) and a-keto aldehydes, into (S)-a-hydroxyacylglutathione. Next, glyoxalase II hydrolyses these a-hydroxy thioesters, producing (S)-a-hydroxy acid derivatives (for example, (S)-lactate and GSH from (S)-lactoyl-GSH). Glyoxalase thereby protects cells from a-oxoaldehyde-mediated formation of advanced glycation.

Enantiomerically pure a-hydroxy thioesters can be used as chiral synthons in asymmetric synthesis of biologically active natural and unnatural compounds. Furthermore, a-hydroxy thioesters by themselves also appear to be vital for diverse pharmaceutical activities including antitumor, anticholinergic, mydriatic and spasmolytic activity. Despite advantageous utility of a-hydroxythioesters, the lack of a general and straightforward catalytic protocol to access enantioenriched a-hydroxy thioesters has hindered their applications in pharmaceutical industry.

Professor Choong Eui SONG and his students (Department of Chemistry) developed an artificial glyoxalase I that successfully catalyzes the enantioselective isomerization of the spontaneously formed hemithioacetal adducts between diverse 2-oxoaldehydes and thiols, as GSH surrogates into chiral a-hydroxy thioesters. This reaction is exceptionally enantioselective and the a-hydroxythioester products are of high value for multiple synthetic applications. The synthetic applicability was highlighted by the coupling reagent-free synthesis of several optically pure a-hydroxyamides, highly important drug candidates in the pharmaceutical industry.

Therapeutic Applications of Biomimetic Catalysis ?

“This biomimetic strategy will provide new scientific insights for developing an artificial enzyme which can outperform the original enzyme. Furthermore, this work would also provide a potential starting point for developing artificial enzymes which might be used for pharmaceutical uses,” says Professor SONG.

The results of this study were published in the one of the world top journal “Nature Communications” (April 04, 2017 / doi: 10.1038/ncomms14877)

* Information about the research paper

- Title: Biomimetic Catalytic Transformation of Toxic a-Oxoaldehydes to High-Value Chiral a-Hydroxythioesters using Artificial Glyoxalase I

- Authors: Sang Yeon PARK (first author, Ph.D. candidate), In-Soo HWANG, Hyun-Ju LEE (co-authors, master course), Choong Eui SONG (corresponding author, professor)

Water enables new catalytic reactions for otherwise unreactive organic reaction

g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS) of mammals. GABA deficiency is associated with several important neurological disorders. In addition, radioactive isotope-labelled b-substituted g-lactams such as [¹¹C]-labeled UCB-J was shown to have excellent PET (positron emission tomography) imaging properties for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders.

Thus, synthesis of many structurally diverse GABA analogs has attracted a great deal of interest in the pharmaceutical field, especially with the aim to increase their lipophilicity and metabolic stability, thus allowing them to gain access to the central nervous system.

Professor Choong Eui SONG and his student (Department of Chemistry) made the important discovery that water enables new catalytic reactions for otherwise unreactive substrate systems. Enantioselective Michael addition of extremely unreactive a,a-disubstituted b-nitroalkenes with malonate derivatives using hydrophobic catalysts, affording both enantiomers of highly enantio-enriched Michael adducts with all-carbon-substituted chiral quaternary centers, has been achieved for the first time. The reaction was made possible by the “on water condition,” which enables enforced hydrophobic interactions between catalysts and substrates due to hydrophobic hydration effects.

-Successful one-pot synthesis of new chiral GABA-analogs with all-carbon quaternary stereogenic centers-

The developed on water protocol was successfully applied for the scalable one-pot syntheses of chiral GABA analogues bearing all-carbon quaternary stereogenic centers at the b-position that might show highly interesting pharmaceutical properties.

This result was recently published in the one of the top journal in the field of chemistry, “Angewandte Chemie International Edition” as a Hot paper. (January 18, 2017 / doi: 10.1002/anie.201611466)

* Information about the research paper

- Title: Water-Enabled Catalytic Asymmetric Michael Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with All-Carbon Quaternary Stereogenic Centers

- Authors: Jae Hun SIM (first author, Ph.D. candidate), Choong Eui SONG (corresponding author, professor)