Hien M. Nguyen
Hien M. Nguyen
Research Interest/Area of Expertise
Carbohydrate Method Development, Oligosaccharide Synthesis, Glycobiology, Fluorination, Radiofluorination for PET Imaging, Catalysis
Hien M. Nguyen was born in Ho Chi Minh City (Saigon), Vietnam. Prof. Nguyen came to the US in 1989 and first settled with his family in Boston, Massachusetts. He graduated with honors from Tufts University in Medford, Massachusetts where he majored in chemistry and conducted research with Professor Marc d'Alarcao. Hien left Boston and moved to attend the University of Illinois at Urbana-Champaign, and he subsequently joined the group of the late David Y. Gin. His PhD thesis focused on developing new carbohydrate methodologies for efficient assembly of complex oligosaccharides. As an NIH postdoctoral fellow in the group of Prof. Barry Trost at Stanford University, Prof. Nguyen pursued training in the area of transition-metal catalysis. Prof. Nguyen began his independent career in 2006 and was promoted with tenure at the University of Iowa. In 2018, he relocated to Wayne State University as the Carl Johnson/Pfizer Endowed Chair and Professor of Chemistry.
Professor Nguyen's research group is focused on new catalytic carbohydrate reaction methods, fluorination and radiofluorination chemistry, as well as chemical biology of heparan sulfate and heparanase.
1) Catalytic Methods for Stereoselective 1,2-Cis Glycosylation
The field of glycoscience has burgeoned in the last several decades, leading to the identification of many oligosaccharides and glycoconjugates which could serve critical roles in a wide range of biological processes. This rapid growth of knowledge about the function of carbohydrates has attracted increasing attention from biological, pharmacological, and medicinal researchers. Meeting their research demands require access to significant quantities of well-defined bioactive carbohydrates. This has prompted resurgence in synthetic interest, with a particular focus on new approaches to construct glycosidic bond. Despite the numerous elegant strategies and methods developed for the formation of glycosidic bonds, stereoselective construction of alpha- and beta-glycosides remains challenging.
We have recently developed novel nickel-catalyzed 1,2-cis-2-amnio glycosylation methods for combining a wide variety of different classes of monosaccharides to produce oligosaccharides bearing 1,2-cis-2-aminosugar motifs in excellent yield and selectivity. The method relies on the nature of the catalyst rather than protecting groups on the substrate to control the selectivity, is broadly applicable to a wide range of substrates, and provides the coupling products in high yields and with excellent selectivity at the newly formed glycosidic bond. In addition, the methods are mild and conducted under operationally simple protocol utilizing sub-stoichiometric amounts of nickel catalyst. The utility of the nickel-catalyzed 1,2-cis-2-amino glycosylation methods have been applied to the synthesis of heparin oligosaccharides, tumor-associated mucin TN-antigen, GPI anchors, and mycothiol.
Currently, we are also developing a series of predictable and stereoselective methods for the construction of the challenging 1,2-cis glycosidic bonds via either photoinduced copper catalysis or organocatalysis (using nitrogen- containing heterocycles as catalysts). The newly developed chemistry is an entirely new mechanistic approach to glycosidation and utilizes the bench-stable catalysts under mild and operationally simple conditions. In addition, this new chemistry does not rely on the nature of the C(2)-protecting or directing groups to control formation of the 1,2-cis glycosidic bond.
2) Chemical Biology of Heparan Sulfate and Heparanase
Heparanase, a beta-endo-glucuronidase, cleaves heparan sulfate (HS) chains at the specific intra-chain sites in the extracellular matrix (ECM). This enzyme is regarded as a regulator of aggressive tumor behavior as clinical studies have showed that raised heparanase levels correlated with increased tumor size, amplified angiogenesis, enhanced metastasis, inflammation, and poor prognosis. As such, heparanase is a leading target for the treatment of cancers and other diseases. Interaction of heparanase with HS is regulated by specific substrate N- and O-sulfation patterns. Although the crystal structure of human heparanase has been recently resolved, a systematic understanding of how this enzyme reads the sulfation pattern of HS substrates at each subsites of heparanase and selects favorable hydrolysis sites remains lacking. This difficulty is due to lack of technology for preparing specific and defied sulfated oligosaccharides. In addition, carbohydrate-based heparanase inhibitors have been developed, but none is translated into clinical use. These inhibitors are heparin-modified molecules, therefore, heterogeneous in size and sulfation patterns, which can lead to unforeseen adverse effects.
To address these challenges, we are developing a new modular chemical approach for the parallel combinatorial synthesis of a library of HS oligosaccharides, representing all possible O- and N-sulfation motifs. Our strategy provides a systematic understanding of substrate specificity for heparanase and how this enzyme selects favorable cleavage site. Furthermore, this study provides an attractive starting point for the design and development of heparanase-inhibiting sulfated oligosaccharides of high efficacy and clinical applicability.
3) Nucleophilic Fluorination and Radiofluorination for PET Imaging
Over the past decade, fluorine-containing molecules have become increasingly important in several fields including medicinal chemistry, positron emission tomography (PET) imaging, agriculture, and materials science. The introduction of carbon-fluorine bonds into organic molecules can lead to improved bioavailability and, in turn, the efficacy of fluorinated drug candidates over their non-fluorinated parent compounds by affecting a wide variety of properties including pKa, lipophilicity, metabolic stability, and binding affinity. Roughly 30% of agrochemicals and 20% of pharmaceutical targets currently on the market contain at least one fluorine atom. As such, numerous methods have been developed to address the unmet challenges previously associated with the syntheses of aryl fluorides and enantioenriched aliphatic fluorides via nucleophilic fluorination. Allylic fluorides are biologically important and can be found in many pharmaceuticals and PET radiotracers. However, catalytic asymmetric methods for the direct nucleophilic incorporation of fluoride into allylic systems remain underdeveloped. Our program involves the discovery of new methods for the regio- and enantioselective synthesis of allylic fluorides via iridium-catalyzed fluorination of trichloroacetimidate substrates. In 2011, we have developed a branched-selective fluorination of allylic trichloroacetimidates utilizing [IrCl(COD)]2 and Et3N·3HF. Recently, we extend the method to the dynamic kinetic asymmetric transformations of racemic allylic trichloroacetimidate substrates catalyzed a chiral diene-ligated iridium catalyst to allylic fluorides with excellent levels of asymmetric induction (90-97% ee).
Recently, we have developed a rapid incorporation of fluorine-18 into allylic systems of organic molecules utilizing iridium catalyst in a combination with [18F]KF.kryptofix complex for use as PET tracers. Under our radiofluorination conditions, the use of [18F]KF.kryptofix allows 18F-incorporation into allylic systems within 5-10 minutes at room temperature with excellent radiochemical yield and specific activity. We continue our efforts by applying this reaction to the radiochemical synthesis of [18F]-labeled PET imaging agents. In addition, we explore the use of allylic [18F]fluorides generated as [18F]-based reagents for utilization in site-specific modification of the peptides and carbohydrates.
Education – Degrees, Licenses, Certifications
- B.S. Tufts University, 1996
- Ph.D. University of Illinois at Urbana-Champaign, 2003
- NIH Postdoctoral Fellow, Stanford University, 2003 - 2006
- Sletten, E. T.; Loka, R. S.; Yu, F.; Nguyen, H. M. "Glycosidase Inhibitors from Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymer." Biomacromolecules 2017, 18, 3387-3399.
- Loka, R. S.; Yu, F.; Sletten, E. T.; Nguyen, H. M. "Design, Synthesis, and Evaluation of Heparan Sulfate Mimicking Glycopolymers for Inhibiting Heparanase Activity." Chem. Commun. 2017, 53, 9163-9166.
- Zhang, Q.; Stockdale, D. P.; Mixdorf, J. C.; Topczewski, J. J.; Nguyen, H. M. "Iridium-Catalyzed Enantioselective Fluorination of Racemic. Secondary Trichloroacetimidates." J. Am. Chem. Soc. 2015, 137, 11912-11915.
- Yu, F.; McConnell, M. S.; Nguyen, H. M. "Scalable Synthesis of Fmoc-Protected GalNAc-Threonine Amino Acid and TN Antigen via Nickel Catalysis." Org. Lett. 2015, 17, 2018-2021.
- Zhang, Q.; Nguyen, H. M. "Rhodium-Catalyzed Regioselective Ring Opening of Vinyl Epoxides with Et3N·3HF: Formation of Allylic Fluorohydrins." Chem. Sci. 2014, 5, 291-296.
- McConnell, M. S.; Yu, F.; Nguyen, H. M. "Nickel-Catalyzed alpha-Glycosylation of C(1)-Hydroxyl Group of Inositol Acceptors: A Formal Synthesis of Mycothiol." Chem. Commun. 2013, 49, 4313-4315.
- Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. "Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates." J. Am. Chem. Soc. 2011, 133, 19318-19321.
- Mensah, E. A.; Yu, F.; Nguyen, H. M. "Nickel-Catalyzed Stereoselective Glycosylation with C(2)-N-Substituted Benzylidene Glycosyl Trichloroacetimidates for the Formation of 1,2-cis-2-Amino Glycosides. Applications to the Synthesis of Heparin Oligosaccharides, GPI Anchor Pseudodisaccharides, and alpha-GalNAc." J. Am. Chem. Soc. 2010, 132, 14288-14302.
CHM 4850 Frontiers in Chemistry, 1 credit hour, W2019
CHM 7220 Organic Reactions & Sythesis, 3 credit hours, W2019
CHM 8850 Frontiers in Chemistry, 1 credit hour, W2019
CHM 1240 Organic Chemistry 1, 4 credit hours, F2018