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Research Overview
Our research group is focusing on three major research areas, and they are: (i) Design, synthesis and evaluation of bioactive natural products and small molecules; (ii) Design, synthesis and application of beltenes and nanotubes; and (iii) Lipid derived biopolymers.
Natural product synthesis constitutes a challenging field in organic chemistry. Our goals are to develop novel biologically active lead compounds for the development of drug candidates through the synthesis and bioevaluaiton of natural products and their simplified structures. A number of biologically active small molecules were discovered by our collaborators and my research group.
(1) Tricyclic pyrones were developed through the studies of the total synthesis of pyripyropene A. This class of compounds, such as CP2, protects neuron cell death from intracellular induced amyloid beta peptides and extracellularly applied oligomeric amyloid beta peptides [1-5]. Moreover, CP2 and its analogs prevent aggregation and cholesterol accumulation in neurons expressing mutant huntingtin protein. Surface plasmon resonance, atomic force microscopy, circular dichroism, multi-dimensional NMR spectroscopy, and protein quantification are used to study amyloid beta peptide oligomerization and disaggregation of oligomers from CP2 and its analogs. Results suggest that CP2 and its analogs may serve as lead compounds for the development of drugs for Alzheimer and Huntington’s diseases.
We have also found that pyridine containing tricyclic pyrones, such as 3-(3-pyridyl)-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran (3-Pyr-TP), are cytotoxic to tumor cells with IC50 values in the nanomolar to micromolar ranges [6]. The tricyclic and tetracyclic pyrones were synthesized from a one-pot condensation of 4-hydroxypyrones with various cyclic enals [7].
A new class of aldose reductase inhibitors, such as {1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran-3-yl}acetic acid, effectively prevents the development of cataracts and diabetic retinopathy in animal models in low concentrations [8,9].
(2) During the study of the total synthesis of (+)-chloropuupehenone, we found a readily available synthetic intermediate, 8-epichloropuupehenol, inhibits lymphatic and intestinal absorption of cholesterol in vivo [10].
(3) Our research group has also embarked onto the total synthesis of ovalicin and its analogs for finding small molecules against Trypanosoma brucei parasite and inhibiting methionine aminopeptidase-2. Our synthetic intermediates inhibit the growth of Trypanosoma brucei in nanomolar ranges, which may be used as lead compounds for the discovery of drugs to treat sleeping sickness.
(4) We are currently pursuing the total synthesis of (+)-myriceric acid A and working on the development of potent endothelin receptor antagonists for the prevention and treatment of various diseases including pulmonary arterial hypertention, control of renal function, vascular disorders, bronchopulmonary disorders, and gastronin-testinal disorders.
Molecular machines, cyclacenes, and carbon nanotubes are fascinating and synthetically challenging subjects. Self-assembled nanotubes and molecular machines derived from substituted beltenes and cyclacenes containing a wide range of structural and functional capabilities will improve our fundamental understanding of non-covalent interactions, and provide new applications in chemical, biological and materials sciences. Our group has been working on these synthetically challenging molecules for the past years. It is interested to note that during our synthetic endeavor, a number of triptycene bisquinones and 1,4-anthraquinones were found to possess potent antitumor activities [11-15].
Selected Publications
1. A novel tricyclic pyrone compound is a candidate small-molecule b-amyloid aggregation inhibitor. Izumi Maezawa, Hui-Chuan Wu, Takeo Iwamoto, Hyun-Seok Hong, Gary A. Radke, Srinivas K. Battina, Sandeep Rana, Erik Pettersson, George M. Martin, Duy H. Hua, and Lee-Way Jin. J. Neurochem. 2006, 98, 57-67.
2. Syntheses and Bioactivities of Tricyclic Pyrones. Duy H. Hua, Xiaodong Huang, Masafumi Tamura, Yi Chen, Melissa Woltkamp, Lee-Way Jin, Elisabeth M. Perchellet, Jean-Pierre Perchellet, Peter K. Chiang, Ichiji Namatame, and Hiroshi Tomoda. Tetrahedron, 2003, 59(26), 4795 - 4803.
3. Novel Tricyclic Pyrone Compounds Prevent Intracellular APP C99-induced Cell Death. Lee-Way Jin, Duy H. Hua, Fang-Shiun Shie, Izumi Maezawa, Bryce Sopher, and George M. Martin. Journal of Molecular Neuroscience 2002, 19, 57-61.
4. Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death. Lee-Way Jin, Duy H. Hua, F. S. Shie, I. Maezawa, B. Sopher, George M. Martin. (2002) In: Drug Discovery and Development for Alzheimer’s Disease. HM Fillit, AW O’Connell, eds. Springer, New York, New York. Page 89-97.
5. A rapid MTT formazan exocytosis assay for screening compounds inhibiting Ab oligomer toxicities. Hyun-Seok Hong, Izumi Maezawa, Nianhuan Yao, Ruben Diaz-Avalos, Sandeep Rana, Duy H. Hua, R. Holland Cheng, Kit S. Lam, and Lee-Way Jin. J. Neurochem.2006, submitted.
6. Tricyclic Pyrone Analogs: A New Synthetic Class of Bifunctional Anticancer Drugs That Inhibit Nucleoside Transport, Microtubule Assembly, the Viability of Leukemic Cells In Vitro, and the Growth of Solid Tumors In Vivo. Elisabeth Perchellet, James Ladesich, Molly Magill, Yi Chen, Duy H. Hua, and Jean-Pierre Perchellet. Anti-Cancer Drugs, 1999, 10, 489-504.
7. A One-Pot Condensation of Enals and Pyrones. Synthesis of Novel 1H,7H-5a,6,8,9-Tetrahydro-1- oxopyrano[4,3-b][1]benzopyrans. Duy H. Hua, Yi Chen, Hong-Sig Sin, Maria J. Maroto, Paul D. Robinson, Steven W. Newell, Elisabeth M. Perchellet, James B. Ladesich, Jonathan A. Freeman, Jean-Pierre Perchellet, and Peter K. Chiang. J. Org. Chem. 1997, 62, 6888-6896.
8. Synthesis and Evaluation of Novel Aldose Reductase Inhibitors: Effects on lens protein kinase Cg. Sarah Lewis, J. Karrer, S. Saleh, Yi Chen, Zheng Tan, Duy H. Hua, James McGill, Yuan-Ping Pang, Brad Fenwick, Alan Brightman, Dolores J. Takemoto. Molecular Vision,2001, 7, 164-171.
9. Normalization of lens protein kinase Cg in galactosemic dogs by a novel aldose reductase inhibitor. Dolores J. Takemoto, Richard Harris, Al Brightman, John McGill, Duy H. Hua, Harriet Davidson, Brad Fenwick, and Lynn M. Wagner. Veterinary Ophthalmology, 2004, 7, 163-167.
10. Total Syntheses of (+)-Chloropuupehenone and (+)-Chloropuupehenol, and their Analogs, and Evaluation of their Bioactivities. Duy H. Hua, Xiaodong Huang, Yi Chen, Srinivas K. Battina, Masafumi Tamura, Sang-Kyu No, Sung I Koo, Ichiji Namatame, Hiroshi Tomoda, Elisabeth M. Perchellet, and Jean-Pierre Perchellet. J. Org. Chem. 2004, 69(18), 6065-6078.
11. Syntheses and Bioactivities of Substituted 9,10-Dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetraones. Unusual Reactivities With Amines. Duy H. Hua, Masafumi Tamura, Xiaodong Huang, Heidi A. Stephany, Bonnie J. Sperfslage, Elizabeth M. Perchellet, Jean-Pierre Perchellet, Suping Jiang, Dennis E. Kyle, and Peter K. Chiang. J. Org. Chem.2002, 67, 2907-2912.
12. Syntheses, Molecular Targets and Antitumor Activities of Novel Triptycene Bisquinones and 1,4-Anthracenedione Analogs. Duy H. Hua, Kaiyan, Lou, Srinivas K. Battina, Huiping Zhao, Elisabeth M. Perchellet, Yang Wang, and Jean-Pierre Perchellet. Anti-Cancer Agents in Medicinal Chemistry, 2006, 6, 303-318.
13. Synthesis and Anticancer Actitivity of Substituted Anthracene-1,4-diones. Duy H. Hua, Kaiyan Lou,Elisabeth M. Perchellet, Yang Wang, Jean-Pierre Perchellet, and Takeo Iwamoto. Tetrahedron, 2004, 60(45), 10155-10163.
14. Antitumor triptycene analogs induce a rapid collapse of mitochondrial transmembrane potential in HL-60 cells and isolated mitrochondria. Yang Wang, Elisabeth M. Perchellet, Mary M. Ward, Kaiyan Lou, Huiping Zhao, Srinivas K. Battina, Bernard Wiredu, Duy H. Hua, and Jean-Pierre Perchellet. International Journal of Oncology, 2006, 28(1), 161-172.
15. Rapid collapse of mitochondrial transmembrane potential in HL-60 cells and isolated mitochondria treated with antitumor 1,4-anthracenediones. Yang Wang, Elisabeth M. Perchellet, Mary M. Ward, Kaiyan Lou, Duy H. Hua, Jean-Pierre Perchellet. Anti-Cancer Drugs, 2005, 16, 953-967.
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