Tricyclic compounds containing nonenolizable cyano enones. A novel class of highly potent anti-inflammatory and cytoprotective agents

Journal of Medicinal Chemistry

Volumn 54, Issue 6, 2011, Pages 1762-1778

  Honda, Tadashi ^a,c   Yoshizawa, Hidenori ^a   Sundararajan, Chitra ^a   David, Emilie ^a   Lajoie, Marc J ^a   Favaloro Jr , Frank G ^a   Janosik, Tomasz ^a   Su, Xiaobo ^a   Honda, Yukiko ^a   Roebuck, Bill D ^b   Gribble, Gordon W ^a  

^a Dartmouth College   (United States)

^b DARTMOUTH MEDICAL SCHOOL   (United States)

^c STONY BROOK UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

(4B,8A,10A) 10A ETHYNYL 4B,8,8 TRIMETHYL 3,7 DIOXO 3,4B,7,8,8A,9,10,10A OCTAHYDROPHENANTHRENE 2,6 DICARBONITRILE; ANTIINFLAMMATORY AGENT; BARDOXOLONE; DEXAMETHASONE; HEME OXYGENASE 1; INDUCIBLE NITRIC OXIDE SYNTHASE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; NITRIC OXIDE; NONENOLIZABLE CYANO ENONE DERIVATIVE; PROTECTIVE AGENT; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); TRITERPENOID; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIINFLAMMATORY ACTIVITY; ARTICLE; CELL PROTECTION; CONTROLLED STUDY; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; HEPATOMA CELL; LIVER TUMOR; MACROPHAGE; MOUSE; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

AFLATOXIN B1; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTINEOPLASTIC AGENTS; CELLS, CULTURED; CYTOPROTECTION; ENZYME INDUCTION; HEME OXYGENASE-1; INTERFERON-GAMMA; LIVER; LIVER NEOPLASMS, EXPERIMENTAL; MACROPHAGES; MALE; MICE; NAD(P)H DEHYDROGENASE (QUINONE); NITRIC OXIDE SYNTHASE TYPE II; NITRILES; PENTACYCLIC TRITERPENES; PHENANTHRENES; PRECANCEROUS CONDITIONS; RATS; STEREOISOMERISM; STOMACH; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79952811165     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101445p     Document Type: Article

References (86)

1. Ohshima, H.; Bartsch, H. Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis Mutat. Res. 1994, 305, 253-264 (Pubitemid 24082901)
2. Mameli, L. J. Aspirin and the potential role of prostaglandins in colon cancer Cancer Res. 1992, 52, 5575-5589
3. Nathan, C. F.; Xie, Q. W. Nitric oxide synthases: roles, tolls, and controls Cell 1994, 78, 915-918
4. Seibert, K.; Masferrer, J. Role of inducible cyclooxygenase (COX-2) in inflammation Receptor 1994, 94, 17-23
5. Tamir, S.; Tannenbaum, S. R. The role of nitric oxide (NO) in the carcinogenic process Biochim. Biophys. Acta 1996, 1288, F31-F36
6. Chhatwal, V. J. S.; Ngoi, S. S.; Chan, S. T. F.; Chia, Y. W.; Moochhala, S. M. Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonie mucosa and surrounding peritumoral normal mucosa Carcinogenesis 1994, 15, 2081-2085
7. Misko, T. P.; Trotter, J. L.; Cross, A. H. Mediation of inflammation by encephalitogenic cells: interferon - induction of nitric oxide synthase and cyclooxygenase 2 J. Neuroimmunol. 1995, 61, 195-204
8. Simonian, N. A.; Coyle, J. T. Oxidative stress in neurodegenerative diseases Annu. Rev. Pharmacol. Toxicol. 1996, 36, 83-106 (Pubitemid 26168695)
9. DuBois, R. N.; Radhika, A.; Reddy, B. S.; Entingh, A. J. Increased cyclooxygenase-2 levels in carcinogen-induced rat colon tumors Gastroenterology 1996, 110, 1259-1262 (Pubitemid 26113767)
10. Takahashi, M.; Fukuda, K.; Ohata, T.; Sugimura, T.; Wakabayashi, K. Increased expression of inducible and endothelial constitutive nitric oxide synthases in rat colon tumors induced by azoxymethane Cancer Res. 1997, 57, 1233-1237 (Pubitemid 27152542)
11. Ding, A.; Nathan, C. F.; Graycar, J.; Derynck, R.; Stuehr, D. J.; Srimai, S. Macrophage deactivating factor and transforming growth factors-l, -2, and -3 inhibit induction of macrophage nitrogen oxide synthesis by IFN- J. Immunol. 1990, 145, 940-944 (Pubitemid 20231287)
12. Cruse, I.; Maines, M. D. Evidence suggesting that the two forms of heme oxygenase are products of different genes J. Biol. Chem. 1988, 263, 3348-3353 (Pubitemid 18072793)
13. Maines, M. D.; Trakshel, G. M.; Kutty, R. K. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible J. Biol. Chem. 1986, 261, 411-419 (Pubitemid 16103962)
14. McCoubrey, W. K., Jr; Huang, T. J.; Maines, M. D. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3 Eur. J. Biochem. 1997, 247, 725-732 (Pubitemid 27308655)
15. Hayashi, S.; Omata, Y.; Sakamoto, H.; Higashimoto, Y.; Hara, T.; Sagara, Y.; Noguchi, M. Characterization of rat heme oxygenase-3 gene. Implication of processed pseudogenes derived from heme oxygenase-2 gene Gene 2004, 336, 241-250 (Pubitemid 38891741)
16. Ryter, S. W.; Otterbein, L. E.; Morse, D.; Choi, A. M. Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance Mol. Cell. Biochem. 2002, 234-235, 249-263 (Pubitemid 34777864)
17. Morse, D.; Choi, A. M. Heme oxygenase-1: the "emerging molecule" has arrived Am. J. Respir. Cell Mol. Biol. 2002, 27, 8-16 (Pubitemid 34657385)
18. Takahashi, T.; Morita, K.; Akagi, R.; Sassa, S. Heme oxygenase-1: a novel therapeutic target in oxidative tissue injuries Curr. Med. Chem. 2004, 11, 1545-1561 (Pubitemid 38735796)
19. Alcaraz, M. J.; Fernandez, P.; Guillen, M. I. Anti-inflammatory actions of the heme oxygenase-1 pathway Curr. Pharm. Des. 2003, 9, 2541-2551 (Pubitemid 37236372)
20. Ross, D.; Kepa, J. K.; Winski, S. L.; Beall, H. D.; Anwar, A.; Siegel, D. NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms Chem.-Biol. Interact. 2000, 129, 77-97 (Pubitemid 32061055)
21. Jaiswal, A. K. Antioxidant response element Biochem. Pharmacol. 1994, 48, 439-444 (Pubitemid 24257005)
22. Talalay, P.; Fahey, J. W.; Holtzclaw, W. D.; Prestera, T.; Zhang, Y. Chemoprotection against cancer by phase 2 enzyme induction Toxicol. Lett. 1995, 82-83, 173-179 (Pubitemid 26057505)
23. Joseph, P.; Xie, T.; Xu, Y.; Jaiswal, A. K. NAD(P)H:quinone oxidoreductase1 (DT-diaphorase): expression, regulation, and role in cancer Oncol. Res. 1994, 6, 525-532
24. Benson, A. M.; Hunkeler, M. J.; Talalay, P. Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 5216-5220 (Pubitemid 11195538)
25. 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-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 (Pubitemid 28496657)
26. Honda, T.; Rounds, B. V.; Bore, L.; Finlay, H. J.; Favaloro, F. G., Jr.; 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
27. Suh, N.; Wing, Y.; Honda, T.; Gribble, G. W.; Dmitrovsky, E.; Hickey, W. F.; Maue, R. A.; Place, A. E.; Porter, D. M.; Spinella, M. J.; Williams, C. R.; Wu, G.; Dannenberg, A. J; Flanders, K. C.; Letterio, J. J.; Mangelsdorf, D. J.; Nathan, C. F.; Nguyen, L.; Porter, W. W.; Ren, R. F.; Roberts, A. B.; Roche, N. S.; Subbaramaiah, K.; Sporn, M. B. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid, with potent differentiating, anti-proliferative, and anti-inflammatory activity Cancer Res. 1999, 59, 336-341 (Pubitemid 29048864)
28. Liby, K.; Hock, T.; Yore, M. M.; Suh, N.; Place, A. E.; Risingsong, R.; Williams, C. R.; Royce, D. B.; Honda, T.; Honda, Y.; Gribble, G. W.; Hill-Kapturczak, N.; Agarwal, A.; Sporn, M. B. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling Cancer Res. 2005, 65, 4789-4798 (Pubitemid 40740817)
29. Dinkova-Kostova, A. T.; Liby, K. T.; Stephenson, K. K.; Holtzclaw, W. D.; Gao, X.; Suh, N.; Williams, C.; Risingsong, R.; Honda, T.; Gribble, G. W.; Sporn, M. B.; Talalay, P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 4584-4589 (Pubitemid 40397155)
30. Wang, Y.; Porter, W. W.; Suh, N.; Honda, T.; Gribble, G. W.; Leesnitzer, L. A.; Plunket, K. D.; Mangelsdorf, D. J.; Blanchard, S. G.; Willson, T. M.; Sporn, M. B. A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor - Mol. Endocrinol. 2000, 14, 1550-1556
31. Ito, Y.; Pandey, P.; Place, A.; Sporn, M. B.; Gribble, G. W.; Honda, T.; Khabanda, S.; Kufe, D. The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien- 28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism Cell Growth Differ. 2000, 11, 261-267 (Pubitemid 30347206)
32. Konopleva, M.; Tsao, T.; Ruvolo, P.; Stiouf, I.; Estrov, Z.; Leysath, C. E.; Zhao, S.; Harris, D.; Chang, S.; Jackson, C. E.; Munsell, M.; Suh, N.; Gribble, G.; Honda, T.; May, W. S.; Sporn, M. B.; Andreeff, M. Novel synthetic triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia Blood 2002, 99, 326-335
33. Stadheim, T. A.; Suh, N.; Ganju, N.; Sporn, M. B.; Eastman, A. The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) potently enhances apoptosis induced by tumor necrosis factor in human leukemia cells J. Biol. Chem. 2002, 277, 16448-16455 (Pubitemid 34967657)
34. Ito, Y.; Pandey, P.; Sporn, M.; Datta, R.; Kharbanda, S.; Kufe, D. The novel triterpenoid CDDO induces apoptosis and differentiation of human osteosarcoma cells by a caspase-8 dependent mechanism Mol. Pharmacol. 2001, 59, 1094-1099 (Pubitemid 32381589)
35. Kim, K.; Lotan, R.; Yue, P.; Sporn, M.; Suh, N.; Gribble, G.; Honda, T.; Wu, G.; Hong, W.; Sun, S. Identification of a novel synthetic triterpenoid, methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells Mol. Cancer Ther. 2002, 1, 177-184
36. Pedersen, I.; Kitada, S.; Schimmer, A.; Kim, Y.; Zapata, J.; Charnoneau, L.; Rassenti, L.; Andreeff, M.; Bennett, F.; Sporn, M.; Liotta, L.; Kipps, T.; Reed, J. The triterpenoid CDDO induces apoptosis in refractory CLLB cells Blood 2002, 100, 2965-2972
37. Yates, M. S.; Kwak, M.-K.; Egner, P. A.; Groopma, J. D.; Bodreddigari, S.; Sutter, T. R.; Baumgartner, K. J.; Roebuck, B. D.; Liby, K. T.; Yore, M. M.; Honda, T.; Gribble, G. W.; Sporn, M. B.; Kensler, T. W. Potent protection against aflatoxin-induced tumorigenesis through induction of Nrf2-regulated pathways by the triterpenoid, CDDO-imidazolide Cancer Res. 2006, 66, 2488-2494
38. Liby, K.; Royce, D. B.; Williams, C. R.; Risingsong, R.; Yore, M. M.; Honda, T.; Gribble, G. W.; Dmitrovsky, E.; Sporn, T. A.; Sporn, M. B. The synthetic triterpenoids, CDDO-methyl ester and CDDO-ethyl amide, prevent lung cancer induced by vinyl carbamate in A/J mice Cancer Res. 2007, 67, 2414-2419 (Pubitemid 46548924)
39. Schwartz, S. L.; Denham, D. S. Hurwitz, C. A.; Meyer, C. J.; Pergola, P. E. Bardoxolone Methyl Shown To Improve Renal Function in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus. Presented at the American Diabetes Association Meeting, New Orleans, LA, 2009; Abstract 112-OR.
40. 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 (Pubitemid 40523075)
41. Ahmad, R.; Raina, D.; Meyer, C.; Kharbanda, S.; Kufe, D. Triterpenoid CDDO-Me blocks the NF-B pathway by direct inhibition of IKK- on Cys-179 J. Biol. Chem. 2006, 281, 35764-35769 (Pubitemid 46041307)
42. Yore, M. M.; Liby, K. T.; Honda, T.; Gribble, G. W.; Sporn, M. B. The synthetic triterpenoid, CDDO-imidazole blocks nuclear factor-B activation through direct inhibition of I-B kinase-beta Mol. Cancer. Ther. 2006, 5, 3232-3239 (Pubitemid 46092066)
43. Ahmad, R.; Raina, D.; Meyer, C.; Kufe, D. Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3 Cancer Res. 2008, 68, 2920-2926 (Pubitemid 351556292)
44. Hirota, H.; Nakamura, T.; Tsuyuki, T.; Takahashi, T. Stereoselective total synthesis of (±)-labdane-8-,15-diol and (±)-eperuane-8-,15- diol Bull. Chem. Soc. Jpn. 1988, 61, 4023-4028
45. Dutcher, J. S.; Macmillan, J. G.; Heathcock, C. H. Pentacyclic triterpene synthesis II. Preparation of an AB synthon J. Org. Chem. 1976, 41, 2663-2669
46. Honda, T.; Gribble, G. W.; Suh, N.; Finlay, H. J.; Rounds, B. V.; Bore, L.; Favaloro, F. G., Jr.; 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 (Pubitemid 30305019)
47. Jabin, I.; Revial, G.; Melloul, K.; Pfau, M. Enantioselective syntheses of (2 S,4a S,8a R)-1,1,4a-trimethyldecahydronaphthalen-2-ol [(-)-TMD], (4a S,8a R)-5,5,8a-trimethyloctahydronaphthalen-2(1 H)-one, and (-)-Polywood, through Michael-type reaction of chiral imines Tetrahedron: Asymmetry 1997, 8, 1101-1109 (Pubitemid 27163304)
48. Muzart, J. Synthesis of unsaturated carbonyl compounds via a chromium-mediated allylic oxidation by 70% tert -butylhydroperoxide Tetrahedron Lett. 1987, 28, 4665-4668
49. Kahne, D.; Collum, D. B. Kinetic cyanations of ketone enolates Tetrahedron Lett. 1981, 22, 5011-5014
50. Finkbeiner, H. L.; Stiles, M. Chelation as a driving force in organic reactions. IV. Synthesis of -nitro acids by control of the carboxylation- decarboxylation equilibrium J. Am. Chem. Soc. 1963, 85, 616-622
51. Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar, H. S., III. A simple method for the efficient synthesis of unsaturated -dicarbonyl compounds J. Org. Chem. 1981, 46, 2920-2923
52. Rasmussen, J. R.; Slinger, C. J.; Kordish, R. J.; Newman-Evans, D. D. J. Synthesis of deoxy sugars. Deoxygenation by treatment with N, N -thiocarbonyldiimidazole/tri- n -butylstannane J. Org. Chem. 1981, 46, 4848-4684
53. Heathcock, C. H.; Mahaim, C.; Schlecht, M. F.; Utawanit, T. A synthetic approach to the quassinoids J. Org. Chem. 1984, 49, 3264-3274
54. Clinton, R. O.; Manson, A. J.; Stonner, F. W.; Neumann, H. C.; Christiansen, R. G.; Clarke, R. L.; Ackerman, J. H.; Page, D. F.; Dean, J. W.; Dickinson, W. B.; Carabateas, C. Steroidal[3,2- c ]pyrazoles. II. Androstanes, 19-norandrostanes and their unsaturated analogs J. Am. Chem. Soc. 1961, 83, 1478-1491
55. Johnson, W. S.; Shelberg, W. E. A plan for distinguishing between some five- and six-membered ring ketones J. Am. Chem. Soc. 1945, 67, 1745-1754
56. Honda, T.; Honda, Y.; Yoshizawa, H.; Gribble, G. W. An efficient synthesis of tricyclic compounds, (±)-(4a-,8a-,10a-)-1,2,3,4,4a,6,7,8,8a, 9,10,10a-dodecahydro-1,1,4a-trimethyl-2-oxophenanthrene-8a-carboxylic acid, its methyl ester, and (±)-(4a-,8a-,10a-)-3,4,4a,6,7,8,8a,9,10,10a-decahydro- 8a-hydroxymethyl-1,1,4a-trimethylphenanthren-2(1 H)-one Org. Prep. Proced. Int. 2005, 37, 546-550 (Pubitemid 43046535)
57. Dean, P. D. G. Halogenolysis of methyl glycyrrhetate with lithium iodide-dimethylformamide J. Chem. Soc. C 1965, 6655
58. -2 Tetrahedron Lett. 1984, 25, 5831-5834
59. Node, M.; Nishide, K.; Sai, M.; Fuji, K.; Fujita, E. Hard acid and soft nucleophile systems. 3. Dealkylation of esters with aluminum halide-thiol and aluminum halide-sulfide systems J. Org. Chem. 1981, 46, 1991-1993
60. Bartlett, P. A.; Johnson, W. S. An improved reagent for the o -alkyl cleavage of methyl esters by nucleophilic displacement Tetrahedron Lett. 1970, 11, 4459-4462
61. Ratcliffe, R.; Rodehorst, R. Improved procedure for oxidations with the chromium trioxide-pyridine complex J. Org. Chem. 1970, 35, 4000-4002
62. 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
63. Perni, R. B.; Gribble, G. W. The von Braun reaction between N-tert -butylamides and phosphorus oxychloride. A convenient nitrile synthesis Org. Prep. Proced. Int. 1983, 15, 297-302
64. Omura, K.; Swern, D. Oxidation of alcohols by "activated" dimethyl sulfoxide. A preparative, steric and mechanistic study Tetrahedron 1978, 34, 1651-1660
65. Botteghi, C.; Chelucci, G.; Marchetti, M. Synthesis of optically active aliphatic nitriles from aldehydes and acids Synth. Commun. 1982, 12, 25-33
66. Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Reduction of organic compounds with sodium borohydride-transition metal salt systems: reduction of organic nitrile, nitro and amide compounds to primary amines Tetrahedron Lett. 1969, 10, 4555-4558
67. Barton, D. H. R.; Ives, D. A. J.; Thomas, B. R. A Wolff-Kishner reduction procedure for sterically hindered carbonyl groups J. Chem. Soc. 1955, 2056
68. Mella, M.; Panza, L.; Ronchetti, F.; Toma, L. 1,2-Dideoxy-3,4:5,7-bis- O -(1-methylethylidene)- d-gluco-and d-galacto -hept-1-ynitols: synthesis and conformational studies Tetrahedron 1988, 44, 1673-1678
69. Corey, E. J.; Ruden, R. A. Stereoselective methods for the synthesis of terminal cis and trans enyne units Tetrahedron Lett. 1973, 1495-1499
70. Cai, C.; Vasella, A. Oligosaccharide analog of polysaccharides. Part 3. A new protecting group for alkynes: orthogonally protected dialkynes Helv. Chim. Acta 1995, 78, 732-757
71. Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes, and bromopyridines Tetrahedron Lett. 1975, 4467-4470
72. Paul, D.; Wytko, J. A.; Koepf, M.; Weiss, J. Design and synthesis of a self-assembled photochemical dyad based on selective imidazole recognition Inorg. Chem. 2002, 41, 3699-3704
73. It has been confirmed that 32 is not converted to 31 in the cell culture medium.
74. Dinkova-Kostova, A. T.; Talalay, P.; Sharkey, J.; Zhang, Y.; Holtzclaw, W. D.; Wang, X. J.; David, E.; Schiavoni, K. H.; Finlayson, S.; 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
75. Dinkova-Kostova, A. T.; Holtzclaw, W. D.; Cole, R. N.; Itoh, K.; Wakabayashi, N.; Katoh, Y.; Yamamoto, M.; Talalay, P. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 11908-11913 (Pubitemid 34994497)
76. Honda, T.; David, E.; Mierke, D. F. Monocyclic Cyanoenones and Methods of Use Thereof. WO2010/011782 A1, January 28, 2010.
77. 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
78. Wang, J. S.; Shen, X.; He, X.; Zhu, Y.-R.; Zhang, B.-C.; Wang, J.-B.; Qian, G.-S.; Kuang, S.-Y.; Zarba, A.; Egner, P. A.; Jacobson, L. P.; Munoz, A.; Helzlsouer, K. J.; Groopman, J. D.; Kensler, T. W. Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People's Republic of China J. Natl. Cancer Inst. 1999, 91, 347-354 (Pubitemid 29102334)
79. Part of this work has been reported in preliminary form: Favaloro, F. G., Jr.; 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 (Pubitemid 35192769)
80. Honda, T.; Favaloro, F. G., Jr.; 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. Presented at the 225th National Meeting of the American Chemical Society, New Orleans, LA, March 23-27, 2003.
81. 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
82. Honda, T.; Favaloro, F. G.; Jr.; Gribble, G. W.; Sporn, M. B.; Suh, N. Tricyclic-Bis-enone Derivatives and Methods of Use Thereof. U.S. Patent 7,176,237 B2, February 13, 2007.
83. 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 C8a and cyano enones in rings A and C: highly potent anti-inflammatory and cytoprotective agents J. Med. Chem. 2007, 50, 1731-1734 (Pubitemid 46626584)
84. 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. Presented at the 234th National Meeting of the American Chemical Society, Boston, MA, August 19-23, 2007.
85. Lajoie, M. J.; Honda, T.; David, E.; Sundararajan, C.; Liby, K. T.; Sporn, M. B.; Gribble, G. W. Design and Synthesis of Novel Tricyclic Compounds Having Acetylene Groups at C-8a and Cyano Enones in Rings A and C: Highly Potent Anti-Inflammatory and Cytoprotective Agents. Presented at the 235th National Meeting of the American Chemical Society, New Orleans, LA, April 6-10, 2008.
86. Honda, T.; Sundararajan, C.; Gribble, G. W.; Sporn, M. B.; Liby, K. T. Synthesis and Biological Activities of New Tricyclic-Bis-enones (TBEs). U.S. Patent 7,714,012 B2, May 11, 2010.