Strategic Laboratories

Anti-inflammatory Research Laboratory

 

            

thonda

Director:  Tadashi Honda, PhD.


Phone: (631) 632-7162

Email: tadashi.honda@stonybrook.edu 

   Dr. Honda’s chemistry home page

 

The primary objective of this laboratory is the drug discovery of new anti-inflammatory and cytoprotective agents as well as the new chemistry that is derived from their syntheses and modifications. 

 

  Our initial research focus was on the development of new anti-inflammatory and cytoprotective agents by modifications of naturally occurring pentacyclic triterpenoids.  Amongst these new semisynthetic triterpenoids, bardoxolone methyl (BARD), which potently activates the cytoprotective Keap1/Nrf2/ antioxidant response element (ARE) pathway, was expected to be the first in class drug for the treatment of diabetic nephropathy.  In a multi–center, double–blind, placebo–controlled phase 2b clinical trial, patients treated with BARD experienced a significant increase in estimated glomerular filtration rate (eGFR), compared with no change in the placebo group. However, the phase 3 studies were halted due to the adverse side effects including mortality.

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 Mechanism studies suggest that BARD regulates various proteins regarding inflammation and carcinogenesis, including Keap1, IKKb, and JAK1, to name a few, by reversible Michael addition between the nonenolizable cyanoenone in ring A of BARD and the SH groups of cysteine moieties on these proteins.  On the basis of the information that essential pharmacophores are nonenolizable cyanoenones, we designed tricyclic compounds containing nonenolizable cyanoenones which gave reversible Michael adduct with a SH group.  We have demonstrated that they are also potent activators of the Keap1/Nrf2/ARE pathway. Among such synthetic tricycles, TBE-31 with an ethynyl group shows remarkable features in various in vitro and in vivo bioassays related to inflammation and carcinogenesis, which BARD does not.  Thus, TBE-31 is expected to be a first in class therapeutic for the treatment of diabetic nephropathy as a back-up compound of BARD.  We have already established an improved synthesis of TBE-31, which is suitable for a large scale production at low cost.  We have started the toxicological evaluation of TBE-31 in collaboration with Dr. Dinkova-Kostova (University of Dundee) in the United Kigdom.

 

Our latest research focus is discovery of new anti-inflammatory and cytoprotective agents containing MCE-1 (ring C of TBE-31) as a warhead in collaboration with Dr. James Bliska (Stony Brook University) and Dr. Dale Mierke (Dartmouth College). Recently, we have found that monocyclic cyanoenones (MCEs), which are derived from rings A and C of TBE-31, display unique and interesting features with respect to reactivity (as Michael acceptors) and biological potency.  In a preliminary set of MCEs, one of the most reactive Michael acceptor is MCE-1 but the addition is reversible. For induction of the phase 2 cytoprotective enzyme NQO1 in Hepa 1c1c murine hepatoma cells, MCE-1 demonstrates the highest potency (CD value: 22 nM). This high potency of MCE-1 is really striking because sulforaphane, a Keap1/Nrf2/ARE activator, which is widely used by many research groups worldwide and in many disease models related to inflammation and cancer, has a CD of 200 nM.

 

 Selected Publications

 

 

  • Saito, A.; Zheng, S.; Takahashi, M.; Li, W.; Ojima, I.; Honda, T. An improved synthesis of a hydroxylmethyl tricyclic ketone from cyclohexanone, the key processes for the synthesis of a highly potent anti-inflammatory and cytoprotective agent.  Synthesis 2013, 45, 3255–3258.
  • Saito, A.; Higgins, M.; Zheng, S.; Li, W.; Ojima, I.; Dinkova-Kostova, A. T.; Honda, T. Synthesis and biological evaluation of biotin conjugates of (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydro-phenanthrene-2,6-dicarbonitrile, an activator of the Keap1/Nrf2/ARE pathway, for the isolation of its protein targets.  Bioorg. Med. Chem. Lett. 2013, 23, 5540–5543.
  • Honda, T.; Yoshizawa, H.; Sundararajan, C.; David, E.; Lajoie, M. j.; Favaloro, F. G. Jr.; Janosik, T.; Su, X.; Honda, Y.; Roebuck, B. D.; Gribble, G. W. Tricyclic Compounds Containing Non-enolizable Cyano Enones.  A Novel Class of Highly Potent Anti-inflammatory and Cytoprotective Agents.  J. Med. Chem. 2011, 21, 2188–2191.
  • Dinkova-Kostova, A. T.; Talalay, P.; Sharkey, J.; Zhang, Y.; Holtzclaw, W. D.; Xiu Jun Wang, X. J.; David, E.; Schiavoni, K. H.; Finlayson, S.; Dale F. Mierke, D. F.; Honda, T.  An Exceptionally Potent Inducer of Cytoprotective Enzymes: Elucidation of the Structural Features that Determine Inducer Potency and Reactivity with Keap1.  J. Biol. Chem. 2010, 285, 33747–33755.  This article was highlighted in a Spotlight section of Chemical Research in Toxicology 2010, 23, 1631–1632.
  • Zheng, S.; Chowdhury, A.; Ojima, I.; Honda, T. Microwave-assisted Diels-Alder reactions between Danishefsky's diene and derivatives of ethyl α-(hydroxymethyl)acrylate. Synthetic approach towards a biotinylated anti-inflammatory monocyclic cyanoenone. Tetrahedron 2013, 69, 2052–2055.
  • Zheng, S.; Resch, D.; Honda, T.; Jasinski, J. P. (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile.  Acta. Cryst. 2012, E68, 3095–3096.
  • Kalra, S.; Knatko, E. V.; Zhang, Y.; Honda, T.; Yamamoto, Y.; Dinkova-Kostova A. T.Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): implications for protection against UV radiation during thiopurine therapy.  Cancer Prev. Res. 2012, 5, 973–981.
  • Zheng, S; Laxmi, Y. R. S.;David, E; Dinkova-Kostova, A. T.; Katherine H. Shiavoni, K. H.; Ren, Y.; Zheng, Y.; Trevino, I.; Bumeister, R.; Ojima, I.; Wigley, W. C.; James J. B.; Mierke, D. F.; Honda, T.  Synthesis, chemical reactivity as Michael acceptors, and biological potency of monocyclic cyanoenones, novel and highly potent anti-inflammatory and  cytoprotective agents. J. Med. Chem. 2012, 55, 4837–4846.
  • Liby, K.; Yore, M. M.; Roebuck B. D.; Baumgartner, K. J.; Honda, T.; Sundararajan, C.; Yoshizawa, H.; Gribble, G. W.; Williams, C. R.; Risingsong, R.; Royce, D. B.; Dinkova-Kostova, A. T.; Stephenson, K. K.; Egner, P. A.; Yates, M. S.; Groopman, J. D.; Kensler, T. W.; Sporn, M. B.  A Novel Acetylenic Tricyclic Bis-(cyano enone) Potently Induces Phase 2 Cytoprotective Pathways and Blocks Liver Carcinogenesis Induced by Aflatoxin. Cancer Res. 2008, 68, 6727–6732.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.; 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.
  • 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.; 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.; 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.; 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.

 

 

ICB&DD * 717 Chemistry Bldg., Stony Brook University, Stony Brook, NY 11794-3400
Phone: 631.632.1311 * Fax: 631.632.7942  Email: roxanne.brockner@stonybrook.edu 
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