Professor Honda received his B.S. degree in Chemistry in 1974, his M.S. degree in Organic Chemistry in 1976, and his Ph.D. in Organic Chemistry in 1979 from the University of Tokyo. In 1979, he joined the Department of Drug Discovery Chemistry at Suntory Institute for Biomedical Research in Japan and worked there as a drug synthetic chemist (finally senior researcher) for 13 years. In 1991, he joined the Central Pharmaceutical Research Institute at Japan Tobacco Inc. and worked as a chief senior researcher for 3 years. In 1995, he joined Dr. Gribble's laboratory at Dartmouth College as a research associate. In 1998, he joined the research faculty of Dartmouth College. In 2005, he was promoted to Research Associate Professor.

Selected Publications

Tadashi.Honda@dartmouth.edu

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Research Interests

The development of new anti-cancer agents from natural products and the new chemistry that is derived from their syntheses and modifications have been the primary objectives of Professor Honda's research program.

Dr. Honda has been engaged in the discovery of anti-cancer drugs based on natural products for the past 27 years. Amongst several anti-cancer drug candidates that he invented during his pharmaceutical career, 2α-L-arabinopyranosyl-9-hydroxyellipticinium bromide (SUN4599) had been evaluated in phase II clinical trials for the treatment of solid tumors, but failed due to hepatoxicity.

Since Dr. Honda joined Dartmouth College, he has been engaged in the development of new anti-cancer drugs from naturally occurring five-ringed triterpenoids in collaboration with Dr. Michael Sporn, a professor at the Dartmouth Medical School and Dr. Gordon Gribble, a professor of chemistry at Dartmouth College. Their ongoing efforts for the improvement of anti-inflammatory and anti-proliferative activity of oleanolic acid led them to discover 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and related compounds. The methyl ester (CDDO-Me) is presently being evaluated in phase II clinical trials for the treatment of melanoma and pancreatic cancer. Dr. Honda and his collaborators have further explored new structures based on CDDO and different five-ringed triterpenoids.

During the course of these investigations, Dr. Honda has designed three-ringed compounds with similar enone functionalities in rings A and C to those of CDDO, but having a much simpler structure than five-ringed triterpenoids. He and his collaborators have found that they are also a novel class of potent anti-inflammatory, cytoprotective, growth suppressive, and pro-apoptotic compounds. Amongst such three-ringed compounds, TBE-31 with the C-8a ethynyl group is much more potent than CDDO in various bioassays in vitro and in vivo. Thus, further investigation (design, synthesis, biological evaluation, etc.) of new TBE-31 analogues is currently being performed in order to discover analogues having different and/or better features than TBE-31, for example, higher potency and lower toxicity, better bioavailability and different distributions in organs, high water-solubility and so on.

Mechanism studies suggest that CDDO regulates various molecules regarding inflammation, differentiation, apoptosis, and proliferation by reversible Michael addition between the cyano enone functionality of CDDO and the sulfhydryl groups of cysteine moieties on these molecules. Based on this mechanism, Dr. Honda has designed entirely new compounds. The synthesis of these new compounds is presently in progress.

• Honda, T.; Kato, M.; Inoue, M.; Shimamoto, T.; Shima, K.; Nakanishi, T.; Yoshida, T.; Noguchi, T. Synthesis and Antitumor Activity of Quaternary Ellipticine Glycosides, a Series of Novel and Highly Active Antitumor Agents. J. Med. Chem. 1988, 31, 1295-1305.
• Honda, T.; Rounds, B. V.; Gribble, G. W.; Suh, N.; Wang, Y.; Sporn, M. B. Design and Synthesis of 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic Acid, a Novel and Highly Active Inhibitor of Nitric Oxide Production in Mouse Macrophages. Bioorg. Med. Chem. Lett. 1998, 8, 2711-2714.
• Honda, T.; Gribble, G. W.; Suh, N.; Finlay, H. J.; Rounds, B. V.; Bore, L.; Favaloro, Jr., F. G.; Wang, Y.; Sporn, M. B. Novel Synthetic Oleanane and Ursane Triterpenoids with Various Enone Functionalities in Ring A as Inhibitors of Nitric Oxide Production in Mouse Macrophages. J. Med. Chem. 2000, 43, 1866-1877.
• Honda, T.; Rounds, B. V.; Bore, L.; Finlay, H. J.; Favaloro, Jr., F. G.; Suh, N.; Wang, Y.; Sporn, M. B.; Gribble, G. W. Synthetic Oleanane and Ursane Triterpenoids with Modified Rings A and C: A Series of Highly Active Inhibitors of Nitric Oxide Production in Mouse Macrophages. J. Med. Chem. 2000, 43, 4233-4246.
• Honda, T.; Honda, Y.; Favaloro, Jr., F. G.; Gribble, G. W.; Suh, N.; Place, A. E.; Rendi, M. H.; Sporn, M. B. A Novel Dicyanotriterpenoid, 2-Cyano-3,12-dioxooloana-1,9(11)-dien-28-onitrile, Active at Picomolar Concentrations for Inhibition of Nitric Oxide Production. Bioorg. Med. Chem. Lett. 2002, 12, 1027-1030.
• Favaloro, Jr., F. G.; Honda, T.; Honda, Y.; Gribble, G. W.; Suh, N.; Risingsong, R.; Sporn, M. B. Design and Synthesis of Tricyclic Compounds with Enone Functionalities in Rings A and C: A Novel Class of Highly Active Inhibitors of Nitric Oxide Production in Mouse Macrophages. J. Med. Chem. 2002, 45, 4801-4805.
• Honda, T.; Favaloro, F. G., Jr.; Janosik, T.; Honda, Y.; Suh, N.; Sporn, M. B.; Gribble, G. W. Efficient Synthesis of (-)- and (+)-Tricyclic Compounds with Enone Functionalities in Rings A and C. A Novel Class of Orally Active Anti-inflammatory and Cancer Chemopreventive Agents. Org. Biomol. Chem. 2003, 1, 4384-4391.
• Honda, T.; Janosik, T.; Honda, Y.; Han, J.; Liby, K. T.; Williams, C. R.; Couch, R. D.; Anderson, A. C.; Sporn, M. B.; Gribble, G. W. Design, Synthesis, and Biological Evaluation of Biotin Conjugates of 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic Acid for the Isolation of the Protein Targets. J. Med. Chem. 2004, 47, 4923-4932.
• Couch, R. D.; Browning, R. G.; Honda, T.; Gribble, G. W.; Wright, D. L.; Sporn, M. B.; Anderson, A. C. Studies on the Reactivity of CDDO, a Promising New Chemopreventive and Chemotherapeutic Agent: Implications for a Molecular Mechanism of Action. Bioorg. Med. Chem. Lett. 2005, 15, 2215-2219.
• Payette, J. N.; Honda, T.; Yoshizawa, H; Favaloro, F. G. Jr.; Gribble, G. W. A Study on the Base-Catalyzed Reverse Vinylogous Aldol Reaction of (4aβ,5β)-4,4a,5,6,7,8-Hexahydro-5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one under Robinson Annulation Conditions. J. Org. Chem. 2006, 71, 416-419.
• Honda, T.; Yoshizawa, H.; Sundararajan, C.; Gribble, G. W. Synthesis of a Novel Dicyano Abietane Analogue: A Potential Anti-inflammatory Agent. J. Org. Chem. 2006, 71, 3314-3316.
• Honda, T.; Liby, K. T.; Su, X.; Sundararajan, C.; Honda, Y.; Suh, N.; Risingsong, R.; Williams, C. R.; Sporn, M. B.; Gribble, G. W. Design, Synthesis, and Anti-inflammatory Activity Both In Vitro and In Vivo of New Betulinic Acid Analogues Having an Enone Functionality in Ring A. Bioorg. Med. Chem. Lett. 2006, 16, 6306-6309.
• Honda, T.; Sundararajan, C.; Yoshizawa, H.; Su, X.; Honda, Y.; Liby, K. T.; Sporn, M. B.; Gribble, G. W. Novel Tricyclic Compounds Having Acetylene Groups at C-8a and Cyano Enones in Rings A and C: Highly Potent Anti-inflammatory and Cytoprotective Agents. J. Med. Chem. 2007, 50, 1731-1734.