The Hua Research Laboratory
(1) Catalytic asymmetric oxidation of diols, alkenes, and alkanes: Chiral molecules are often needed as synthetic intermediates for the synthesis of chiral drugs and chiral materials. Bimetallic nanoclusters comprising two metals have distinct and greater catalytic properties than those comprising single metals or bulk molecules. Catalytic asymmetric syn-dihydroxylation reactions of alkenes have been investigated greatly in recent years. The avoidance of the use of toxic osmium metal and improving the enantioselectivity by using bimetallic nanoparticles and chiral polymer in the catalytic asymmetric oxidation of alkenes would advance the asymmetric synthesis of diols from alkenes. The study may shed light onto the catalysts through incarceration of bimetallic nanocluster by chiral polymer, the chemistry of chiral stabilizer, and synthetic applicability of the oxidation methodologies. Regio- and enantio-selective C-H oxidation of alkanes and cycloalkanes is one of the most challenging transformations in organic synthesis. Our success in the catalytic asymmetric C-H oxidation of cycloalkanes and complex natural products utilizing Cu/Au-chiral substituted poly-N-vinylpyrrolidinone and hydrogen peroxide has opened a new field for further investigation of their scopes, mechanisms, and application. Moreover, utilization of catalytic amounts of bimetallic nanoclusters/chiral polymer and oxidant in desymmetrized ring closing reactions in C-O and C-N bond forming reactions and imine-Heck cyclization in C-C bond construction have also been discovered.
1. Chiral-substituted poly-N-vinylpyrrolidinones and bimetallic nanoclusters in catalytic asymmetric oxidation reactions. Bo Hao, Medha J. Gunaratna, Man Zhang, Sahani Weeasekara, Sarah N. Seiwald, Vu T. Nguyen, Alex Meier, and Duy H. Hua. J. Am. Chem. Soc. 2016, 138, 16839-16848. DOI: 10.1021/jacs.6b12113.
2. Synthesis and application of chiral substituted polyvinylpyrrolidinones. Duy H. Hua. U.S. Provisional patent application serial No. 62/314,227, awarded: October 5, 2017. International application No. PCT/US17/24533.
3. "Second Generation Chiral Poly-N-vinylpyrrolidinones and Complexes with Bimetallic Nanoclusters and Uses Thereof in Asymmetric Oxidation Reactions". Duy H. Hua. U. S. Provisional Patent Application No. 62/627,841 filed on January 2019.
(2) Discovery of tricyclic pyrone molecules for Alzheimer’s disease (AD): AD is the most common cause of dementia in the elderly. There is an unmet medical need for new AD therapeutic development. Amyloid-b(Ab) deposited in AD brains has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death observed in AD brains. Therefore, designing therapies targetingAband downstream events have become a major effort in AD drug development. We have taken a different approach and synthesized a class of tricyclic pyrone compounds (TPs). The lead compounds CP2 and TP70 were found to have high oral bioavailability, excellent blood–brain barrier permeability, and low toxicity. Administering compounds either orally or intraperitoneally to young AD transgenic models (mice and rats) resulted in substantially reduced soluble and insoluble Abspecies in the brain and preserved memory and motor function. Furthermore, we have found that in addition to being able to block the toxicity and formation of both intraneuronal and extracellular Aβaggregates, the lead TPs also increase cellular cholesterol efflux, restore axonal trafficking, modulate mitochondrial complex I, and enhance hippocampal synaptic placidity through the modulation of NMDA — these synergistic cellular actions could be potential mechanisms underlying in vivo effects.
1. The anti-Aband neuroprotective properties of a novel tricyclic pyrone molecule. Izumi Maezawa, Bende Zou, Jacopo Di Lucente, William S. Cao, Conrado Pascual, Sahani Weerasekara, Man Zhang, Xinmin Simon Xie, Duy H. Hua, and Lee-Way Jin. J. Alzheimer’s Disease, 2017, 58, 559-574. DOI 10.3233/JAD-161175. PMC Journal-In Process.
2. Modulation of mitochondrial complex I activity averts cognitive decline in multiple animal models of familial Alzheimer's Disease. Liang Zhang, Song Zhang, Izumi Maezawa, Sergey Trushin, Paras Minhas, Matthew Pinto, Lee-Way Jin, Keshar Prasain, Thi D. T. Nguyen, Yu Yamazaki, TakahisaKanekiyo, Guojun Bu, Ben Gateno, Kyeong-Ok Chang, Karl A. Nath, Emirhan Nemutlu, Petras Dzeja, Yuan-PingPang, Duy H. Hua, and Eugenia Trushina. EBioMedicine2015, 2, 294-305; doi: 10.1016/j.ebiom.2015.03.009. PMCID: PMC4465115
3. Inhibition of Acyl-CoA: Cholesterol Acyltransferase (ACAT), Overexpression of Cholesterol Transporter Gene, and Protection of Amyloid (A) Oligomers-Induced Neuronal Cell Death by Tricyclic Pyrone Molecules. Laxman Pokhrel, Izumi Maezawa, Thi D. T. Nguyen, Kyeong-Ok Chang, Lee-Way Jin, and Duy H. Hua. J. Med. Chem. 2012, 55(20), 8969-8973; http://dx.doi.org/10.1021/jm3012189.PMCID:PMC3486708
4. Inhibition of Alzheimer’s amyloid toxicity with a tricyclic pyrone molecule In Vitroand In Vivo. Hyun-Seok Hong, Sandeep Rana, Lydia Barrigan, Aibin Shi, Yi Zhang, Feimeng Zhou, Lee-Way Jin, and Duy H. Hua. J. Neurochem. 2009,108, 1097-1108. doi: 10.1111/j.1471-4159.2008.05866.x. PMCID: PMC2748761
(3) Nanocarbon fiber electronic biosensors for the profiling of overexpressed proteases: Early detection of cancers could save many lives, and it remains a challenge for early detection of various cancers including breast cancers. Quantitative detection of molecular biomarkers that are involved in breast tumor progression may lead to early detection of cancer and provide helpful information on the treatment. Cancer metastasis involves proteases, which could serve as biomarkers for diagnosis.Among them, cathepsin B is a representative prognostic marker, and an increase of cathepsin B is found in the plasma of breast cancer patients. In a collaboration with Dr. Jun Li’s laboratory, we have synthesized a number of cathepsin B, capthesin D, Adam 10, and Adam 17 peptide substrates covalently bonded to ferrocene. The peptide substrates attached to the carbon nanofibers of the electronic biosensor chip. When cathepsin B is present in the biosensor chip, a cleavage of the peptide substrate is resulted leading to the release of the ferrocene containing fragment from the carbon nanofiber and a decrease of electronic signal (ferrocene provides the electronic signal) resulted. Using this device the activity and amounts of cathepsin B in tissue or plasma or cell lysate can be detected and quantified, thereby a detection of cathepsin B in breast cancer can be achieved. Profiling of a library of overexpressed proteases in triple-negative breast cancer is used for the detection.
1. Electrochemical Activity Assay for Protease Analysis Using Carbon Nanofiber Nanoelectrode Arrays. Yang Song, Huafang Fan, Morgan J. Anderson, JestinGage Wright, Duy H. Hua, Jessica Koehne, Meyya Meyyappan, and Jun Li. Analytical Chemistry, 2019, in press. DOI: 10.1021/acs.analchem.8b05189
2. Quantitative electrochemical detection of cathepsin B activity in breast cancer cell lysates using carbon nanofiber nanoelectrode arrays toward identification of cancer formation. Luxi Z. Swisher, Medha J. G. A. Gamaralalage, Stephanie Shishido, Foram Madiyar, Thu A. Nguyen, Duy H. Hua, and Jun Li. Nanomedicine: Nanotech. Biol. & Med. 2015,11, 1695-1704. http://dx.doi.org/10.1016/j.nano.2015.04.014, PMCID: NANO1124
3. Luxi Z. Swisher, Allan M. Prior, Thu A. Nguyen,Duy H. Hua, Jun Li. Quantitative electrochemical detection of cathepsin B activity in complex tissue lysates using enhanced AC voltammetry at Carbon Nanofiber Nanoelectrode Arrays. Biosensors & Bioelectronics. 2014, 56, 129-136. http://dx.doi.org/10.1016/j.bios.2014.01.002, NIHMS 556017, PMID:24480132, PMCID:PMC3943551
4. Luxi Z. Swisher, Lateef U. Syed, Allan M. Prior, Kyle Carlson, Thu Annelise Nguyen, Duy H. Hua, and Jun Li. Development of protease biosensor using carbon nanofiber nanoelectrode arrays with enhanced electrochemical performance. J. Phys. Chem. C 2013, 117(8), 4268-4277. dx.doi.org/10.1021/jp312031u. NIHMS445090; PMID: 23814632; PMCID: PMC3694732