Reversible michael additions: Covalent inhibitors and prodrugs

Mini-Reviews in Medicinal Chemistry

Volumn 12, Issue 13, 2012, Pages 1330-1344

  Johansson, Martin H ^a  

^a LUND UNIVERSITY   (Sweden)

Author keywords

Covalent inhibition; Michael addition; Natural products; Prodrug; Reversible

Indexed keywords

AFATINIB; BARDOXOLONE; BREFELDIN A; CANERTINIB; CURCUMIN; CYCLOPENTENONE; EKB 565; ELECTROPHILE; ETACRYNIC ACID; GLUTATHIONE; HYDROGEN SULFITE REDUCTASE; NERATINIB; PELITINIB; PRODRUG; SESQUITERPENE LACTONE; THIOL; UNCLASSIFIED DRUG; WORTMANNIN;

BIOINFORMATICS; CATALYSIS; CHEMICAL REACTION KINETICS; COVALENT BOND; DRUG ACTIVITY; DRUG BINDING; DRUG DESIGN; DRUG MECHANISM; DRUG SYNTHESIS; ELECTROPHILICITY; MICHAEL ADDITION; PROTON TRANSPORT; REVIEW;

DRUG DESIGN; ENZYME INHIBITORS; HUMANS; PRODRUGS;

EID: 84870190055     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/13895575112091330     Document Type: Review

References (107)

1. Doss, G.A.; Baillie, T.A. Addressing metabolic activation as an integral component of drug design. Drug Metab. Rev., 2006, 38, 641-649.
2. Potashman, M. H.; Duggan, M. E. Covalent modifiers: an orthogonal approach to drug design. J. Med. Chem., 2009, 52, 1231-1246.
3. Drahl, C.; Cravatt, B.F.; Sorensen, E.J. Protein-reactive natural products. Angew. Chem. Int. Ed Engl., 2005, 44, 5788-809.
4. Barglow, K.T.; Cravatt, B.F. Activity-based protein profiling for the functional annotation of enzymes. Nat. Methods, 2007, 10, 822-827.
5. Cravatt, B.F.; Wright, A.T.; Kozarich, J.W. Activity-based protein profiling: from enzyme chemistry to proteomic chemistry. Annu. Rev. Biochem., 2008, 77, 383-414.
6. Swinney, D.C.; Anthony, J. How were new medicines discovered? Nat. Rev. Drug. Discov., 2011, 10, 507-519.
7. Copeland, R.A.; Pompliano, D.L.; Meek T.D. Drug-target residence time and its implications for lead optimization. Nat. Rev. Drug. Discov., 2006, 5, 730-739.
8. Swinney, D.C. Biochemical mechanisms of drug action: what does it take for success? Nat. Rev. Drug. Discov., 2004, 3, 801-808.
9. Johnson, D. S.; Weerapana, E.; Cravatt, B. F. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors. Future Med. Chem., 2010, 2, 949-964
10. Smith, A. J. T.; Zhang, X.; Leach, A. G.; Houk, K. N. Beyond picomolar affinities: quantitative aspects of noncovalent and covalent binding of drugs to proteins. J. Med. Chem., 2009, 52, 225-233.
11. Singh, J.; Petter, R. C.; Baillie, T. A.; Whitty, A. The resurgence of covalent drugs Nat. Rev Drug Disc., 2011, 10, 307-317.
12. Fry, D. W.; Bridges, A. J.; Denny, W. A.; Doherty, A.; Gries, K. D.; Hicks, J. L.; Hook, K. E.; Keller, P. R.; Leopold, W. R.; Loo, J. A.; McNamara, D. J.; Nelson, J. M.; Sherwood, V.; Smaill, J. B.; Trumpp-Kallmeyer, S.; Dobrusin, E. M. Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc. Natl. Acad. Sci. U.S.A., 1998, 95, 12022-12027.
13. Singh, J.; Petter, R. C; Kluge, A. F. Targeted covalent drugs of the kinase family Curr. Opin. Chem. Biol., 2010, 14, 475-480.
14. Smaill, J.B.; Rewcastle, G.W.; Loo, J.A.; Greis, K.D.; Chan, O.H.; Reyner, E.L.; Lipka, E.; Showalter, H.D.; Vincent, P, W.; Elliott, W.L.; Denny, W.A. "Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline-and 4-(phenylamino)pyrido3,2-dpyrimidine-6-acrylamides bearing additional solubilizing functions". J. Med. Chem., 2000, 43, 1380-1397.
15. Wissner, A.; Overbeek, E.; Reich, M.F.; Floyd, M.B.; Johnson, B.D.; Mamuya, N.; Rosfjord, E.C.; Discafani, C.; Davis, R.; Shi, X.; Rabindran, S.K.; Gruber, B.C.; Ye, F.; Hallett, W.A.; Nilakantan, R.; Shen, R.; Wang, Y.F.; Greenberger, L.M.; Tsou, H.R. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J. Med. Chem., 2003, 46, 49-63.
16. Tsou, H.R.; Overbeek-Klumpers, E.G.; Hallett, W.A.; Reich, M.F., Floyd, M.B.; Johnson, B.D.; Michalak, R.S.; Nilakantan, R.; Discafani, C.; Golas, J.; Rabindran, S.K.; Shen, R.; Shi, X.; Wang, Y.F.; Upeslacis, J.; Wissner, A. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J. Med. Chem., 2005, 48, 1107-1131.
17. Soyka, R.; Rall, W.; Schnaubelt, J.; Sieger, P.; Kulinna, C. Synthesis of (oxobutenyl)quinazolines and derivatives for treating cancer and other diseases. U.S. Pat. Appl. Publ., 2005, US 20050085495 A1 20050421.
18. Carmi, C.; Cavazzoni, A.; Vezzosi, S.; Bordi, F.; Vacondio, F.; Silva, C.; Rivara, S.; Lodola, A.; Alfieri, R.R.; La Monica, S.; Galetti, M.; Ardizzoni, A.; Petronini, P.G.; Mor, M. Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion. J. Med. Chem., 2010, 53, 2038-2050.
19. Carmi, C.; Galvani, E.; Vacondio, F.; Rivara, S.; Lodola, A.; Russo, S.; Aiello, S.; Bordi, F.; Costantino, G.; Cavazzoni, A.; Alfieri, R.R.; Ardizzoni, A.; Petronini, P.G.; Mor, M. Irreversible inhibition of epidermal growth factor receptor activity by 3-aminopropanamides. J. Med. Chem., 2012, 55, 2251-2264.
20. Miller, V.A.; Hirsh, V.; Cadranel, J.; Chen, Y.M.; Park, K.; Kim, S.W.; Zhou, C.; Su, W.C.; Wang, M.; Sun, Y.; Heo, D.S.; Crino, L.; Tan, E.H.; Chao, T.Y.; Shahidi, M.; Cong, X.J.; Lorence, R.M.; Yang, J.C. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUXLung 1): a phase 2b/3 randomised trial. Lancet Oncol., 2012, 13, 528-538.
21. Yang, J.C.; Shih, J.Y.; Su, W.C.; Hsia, T.C.; Tsai, C.M.; Ou, S.H.; Yu, C.J.; Chang, G.C.; Ho, C.L.; Sequist, L.V.; Dudek, A.Z.; Shahidi, M.; Cong. X.J.; Lorence, R.M.; Yang, P.C.; Miller V.A. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol., 2012, 13, 539-548.
22. Leung, D.; Abbenante, G.; Fairlie, D. P. Protease Inhibitors: Current Status and Future Prospects. J. Med. Chem., 2000, 43, 305-341.
23. Groll, M.; Berkers, C.R.; Ploegh, H.L.; Ovaa, H. Crystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure, 2006, 14, 451-456.
24. Thompson, S.A.; Andrews, P.R.; Hanzlik, R.P. Carboxyl-modified amino acids and peptides as protease inhibitors. J. Med. Chem., 1986, 29, 104-111.
25. Pande, V.; Sousa, S. F.; Ramos, M. J. Direct Covalent Modification as a Strategy to Inhibit Nuclear Factor-Kappa B. Curr. Med. Chem., 2009, 16, 4261-4273.
26. Luo, Y.; Eggler, A.L.; Liu, D.; Liu, G.; Mesecar, A.D.; van Breemen, R.B. Sites of alkylation of human Keap1 by natural chemoprevention agents. J. Am. Soc. Mass. Spectrom., 2007, 18, 2226-2232.
27. Magesh, S.; Chen, Y.; Hu, L. Small Molecule Modulators of Keap1-Nrf2-ARE Pathway as Potential Preventive and Therapeutic Agents. Med. Res. Rev. 2012, 32 (4), 687-726.
28. Amslinger, S. The Tunable Functionality of, κ-Unsaturated Carbonyl Compounds Enables Their Differential Application in Biological Systems Chem. Med. Chem., 2010, 5, 351-356.
29. Gupta, P.; Sharma, U.; Schulz, T. C.; Sherrer, E. S.; McLean, A. B.; Robins, A. J; West, L. M. Bioactive diterpenoid containing a reversible "spring-loaded" (E, Z)-dieneone Michael acceptor. Org. Lett., 2011, 13, 3920-3923.
30. Meister, A.; Anderson, M.E. Glutathione. Annu. Rev. Biochem., 1983, 52, 711-760.
31. Baillie, T. A.; Slatter, J. G.; Glutathione: a vehicle for the transport of chemically reactive metabolites in vivo. Acc. Chem. Res.,1991, 24, 264-270.
32. van Bladeren, P. J. Glutathione conjugation as a bioactivation reaction Chem. Biol. Interact., 2000, 129, 61-76
33. Esterbauer H.; Zollner, H.; Scholz, N. Reaction of glutathione with conjugated carbonyls Z. Naturforsch. C, 1975, 30, 66-73.
34. Trujillo, M.; Radi, R. Peroxynitrite reaction with the reduced and the oxidized forms of lipoic acid: new insights into the reaction of peroxynitrite with thiols. Arch. Biochem. Biophys., 2002, 397, 91-98.
35. Krenske, E. H.; Petter, R. C.; Zhu, Z.; Houk, K. N. Transition states and energetics of nucleophilic additions of thiols to substituted, κ-unsaturated ketones: substituent effects involve enone stabilization, product branching, and solvation. J. Org. Chem., 2011, 76, 5074-5081.
36. Schwöbel, J. A. H.; Madden, J. C.; Cronin, M. T. D. Examination of Michael addition reactivity towards glutathione by transition-state calculations. SAR QSAR Environ. Res., 2010, 21, 693-710.
37. Allen, C. F. H; Humphlett, W.J. The thermal reversibility of the Michael reaction. Can. J. Chem., 1966, 44, 2315-2321.
38. Van Axel Castelli, V.; Bernardi, F.; Dalla Cort, A.; Mandolini, L.; Rossi, I.; Schiaffino, L. Rates and Equilibria of the Michael-Type Addition of Benzenethiol to 2-Cyclopenten-1-ones. J. Org. Chem., 1999, 64, 8122-8126.
39. Enoch, S.J.; Cronin, M.T.D.; Schultz, T.W.; Madden, J.C. Quantitative and Mechanistic Read Across for Predicting the Skin Sensitization Potential of Alkenes Acting via Michael Addition. Chem. Res. Toxicol., 2008, 21, 513-520
40. Lin, D.; Saleh, S.; Liebler, D. C. Reversibility of covalent electrophileprotein adducts and chemical toxicity. Chem. Res. Toxicol., 2008, 21, 2361-2369.
41. Mutus, B.; Wagner, J. D.; Talpas, C. J.; Dimmock, J. R.; Phillips, O. A.; Reid, R. S. 1-p-chlorophenyl-4,4-dimethyl-5-diethylamino-1-penten-3-one hydrobromide, a sulfhydryl-specific compound which reacts irreversibly with protein thiols but reversibly with small molecular weight thiols. Anal. Biochem., 1989, 177, 237-243.
42. Vroomen, L. H. M; Berghmans, M. C. J.; Groten, J. P.; Koeman, J. H.; Van Bladeren, P. J. Reversible interaction of a reactive intermediate derived from furazolidone with glutathione and protein. Toxicol. Appl. Pharm., 1988, 95, 53-60.
43. Smith, I. H.; Wood, E. J.; Casida, J. E. Glutathione conjugate of the pyrethroid tetramethrin. J. Agric. Food Chem., 1982, 30, 598-600.
44. Henderson, A. P.; Bleasdale, C.; Delaney, K.; Lindstrom, A. B.; Rappaport, S. M.; Waidyanatha, S.; Watson, W. P.; Golding, B. T. Evidence for the formation of Michael adducts from reactions of (E, E)-muconaldehyde with glutathione and other thiols. Bioorg. Chem., 2005, 33, 363-373.
45. Lee, B.; Bauer, H.; Melchers, J.; Ruppert, T.; Rattray, L.; Yardley, V.; Davioud-Charvet, E.; Krauth-Siegel, R. L. Irreversible inactivation of trypanothione reductase by unsaturated Mannich bases: a divinyl ketone as key intermediate. J. Med. Chem., 2005, 48, 7400-7410.
46. Davioud-Charvet, E.; McLeish, M. J.; Veine, D. M.; Giegel, D.; Arscott, L. D.; Andricopulo, A. D.; Becker, K.; Muller, S.; Schirmer, R. H.; Williams, C. H., Jr.; Kenyon, G. L. Mechanism-based inactivation of thioredoxin reductase from Plasmodium falciparum by Mannich bases. Implication for cytotoxicity. Biochemistry, 2003, 42, 13319-13330.
47. Connors, T.A.; Cox, P.J.; Farmer, P.B.; Foster, A.B.; Jarman, M. Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol., 1974, 23, 115-129.
48. Chandrasekaran, A.; Shen, L.; Lockhead, S.; Oganesian, A.; Wang, J.; Scatina, J. Reversible covalent binding of neratinib to human serum albumin in vitro. Drug. Metab. Lett., 2010, 4, 220-227.
49. Chu, W.; Rothfuss, J.; Chu, Y.; Zhou, D.; Mach, R.H. Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6. J. Med. Chem., 2009, 52, 2188-2191.
50. Chu, W.; Rothfuss, J.; D'Avignon, A.; Zeng, C.; Zhou, D.; Hotchkiss, R. S.; Mach, R. H. Isatin sulfonamide analogs containing a Michael addition acceptor: a new class of caspase 3/7 inhibitors. J. Med. Chem., 2007, 50, 3751-3755.
51. Cutshall, N.S.; O'Day, C.; Prezhdo, M. Rhodanine derivatives as inhibitors of JSP-1. Bioorg. Med. Chem. Lett., 2005, 15, 3374-3379.
52. Erman, A.; Neéman, I. Inhibition of phosphofructokinase by the toxic cembranolide sarcophine isolated from the soft-bodied coral Sarcophyton glaucum. Toxicon., 1977, 15, 207-215.
53. Lambert, J.M.; Gorzov, P.; Veprintsev, D.B.; Söderqvist, M.; Segerbäck, D.; Bergman, J.; Fersht, A.R.; Hainaut, P.; Wiman, K.G.; Bykov, V.J. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell, 2009, 15, 376-388.
54. Talalay, P.; De Long, M. J.; Prochaska, H. J. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 8261-8265.
55. Rudolph T. K.; Freeman B. A. Transduction of redox signaling by electrophile-protein reactions. Science Signaling, 2009, 2 (90), re7.
56. Pati, H. N.; Das, U.; Sharma, R. K.; Dimmock, J. R. Cytotoxic thiol alkylators, Mini-Rev. Med. Chem., 2007, 7 131-139.
57. Natsch, A.; Haupt, T.; Laue, H. Relating skin sensitizing potency to chemical reactivity: reactive Michael acceptors inhibit NF-ΔB signaling and are less sensitizing than S(N)Ar-and S(N)2-reactive chemicals. Chem. Res. Toxicol., 2011, 24, 2018-2027.
58. Lee, Y.; Shin, D.H.; Kim, J.H.; Hong, S.; Choi, D.; Kim, Y.J.; Kwak, M.K.; Jung, Y. Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaB kinase inhibition are involved in NFkappaB inhibitory effect: structural analysis for NFkappaB inhibition. Eur. J. Pharmacol., 2010, 643, 21-28.
59. Dinkova-Kostova, A.T.; Cory, A.H.; Bozak, R.E.; Hicks, R.J.; Cory, J.G. Bis(2-hydroxybenzylidene)acetone, a potent inducer of the phase 2 response, causes apoptosis in mouse leukemia cells through a p53-independent, caspase-mediated pathway. Cancer Lett., 2007, 245, 341-349.
60. Itoh, T.; Fairall, L.; Amin, K.; Inaba, Y.; Szanto, A.; Balint, B.L.; Nagy, L.; Yamamoto, K.; Schwabe, J.W. Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat. Struct. Mol. Biol., 2008, 15, 924-931.
61. Hinman, A.; Chuang, H.H.; Bautista, D.M.; Julius, D. TRP channel activation by reversible covalent modification. Proc. Natl. Acad. Sci. U.S.A., 2006, 103, 19564-19568.
62. Freeman, B. A.; Baker, P. R. S.; Schopfer, F. J.; Woodcock, S. R.; Napolitano, A.; d'Ischia, M. Nitro-fatty Acid Formation and Signaling. J. Biol. Chem., 2008, 283, 15515-15519.
63. Batthyany, C.; Schopfer, F. J.; Baker, P. R. S.; Rosario Durán, R.; Baker, L. M. S.; Huang, Y.; Cerveñansky, C.; Branchaud, B. P.; Freeman, B. A. Reversible Post-translational Modification of Proteins by Nitrated Fatty Acids in Vivo. J. Biol. Chem., 2006, 281, 20450-20463.
64. Baker, L. M. S.; Baker, P. R. S.; Golin-Bisello, F., Schopfer, F. J.; Fink, M.; Woodcock, S. R.; Branchaud, B. P.; Radi, R.; Freeman, B. A. Nitro-fatty Acid Reaction with Glutathione and Cysteine: Kinetic Analysis of Thiol Alkylation By a Michael Addition Reaction. J. Biol. Chem., 2007, 282, 31085-31093.
65. Wondrak, G. T. Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities. Antioxid. Redox Signal., 2009, 11, 3013-3069.
66. Na, H.K.; Surh, Y.J. Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection. Mol. Carcinog., 2006, 45, 368-380.
67. Xie, Y.; Kole, S.; Precht, P.; Pazin, M.J.; Bernier, M. Sglutathionylation impairs signal transducer and activator of transcription 3 activation and signaling. Endocrinology, 2009, 150, 1122-1131.
68. Switzer, C.H.; Cheng, R.Y.; Ridnour, L.A.; Murray, M.C.; Tazzari, V.; Sparatore, A.; Del Soldato, P.; Hines, H.B.; Glynn, S.A.; Ambs, S.; Wink, D.A. Dithiolethiones Inhibit NF-ΔB Activity via Covalent Modification in Human Estrogen Receptor-Negative Breast Cancer. Cancer Res., 2012, 72, 2394-2404.
69. Perkins, N.D. Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene, 2006, 25, 6717-6730.
70. Kim, D.H.; Kundu, J.K.; Surh, Y.J. Redox modulation of p53: mechanisms and functional significance. Mol. Carcinog., 2011, 50, 222-234.
71. Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. Tumor inhibitors. 69. Structure-cytotoxicity relationships among the sesquiterpene lactones. J. Med. Chem., 1971, 14, 1147-1152.
72. Schmidt, T. J.; Lyß, G.; Pahl, H. L.; Merfort, I. Helenanolide type sesquiterpene lactones. Part 5: the role of glutathione addition under physiological conditions. Bioorg. Med. Chem., 1999, 7, 2849-2855.
73. Neelakantan, S.; Nasim, S.; Guzman, M. L.; Jordan, C. T.; Crooks, P. A. Aminoparthenolides as novel anti-leukemic agents: Discovery of the NF-ΔB inhibitor, DMAPT (LC-1). Bioorg. Med. Chem. Lett., 2009, 19, 4346-4349.
74. Hwang, D.-R.; Wu, Y.-S.; Chang, C.-W.; Lien, T.-W.; Chen, W.-C.; Tan, U.-K.; Hsu, J. T. A.; Hsieh, H.-P. Synthesis and anti-viral activity of a series of sesquiterpene lactones and analogs in the subgenomic HCV replicon system. Bioorg. Med. Chem., 2006, 14, 83-91.
75. Woods, J.R.; Mo, H.; Bieberich, A.A.; Alavanja, T.; Colby, D.A. Fluorinated Amino-Derivatives of the Sesquiterpene Lactone, Parthenolide, as 19F NMR Probes in Deuterium-Free Environments. J. Med. Chem., 2011, 54, 7934-7941.
76. Lawrence, N. J.; McGowan, A. T.; Nduka, J.; Hadfield, J. A.; Pritchard, R. G. Cytotoxic Michael-Type Amine Adducts of κ-Methylene Lactones Alantolactone and Isoalantolactone. Bioorg. Med. Chem. Lett., 2001, 11, 429-431.
77. Hejchman, E.; Haugwitz, R. D.; Cushman, M. Synthesis and cytotoxicity of · water-soluble ambrosin prodrug candidates. J. Med. Chem., 1995, 38, 3407-3410.
78. Heilmann, J.; Wasescha, M. R.; Schmidt, T. J. The influence of glutathione and cysteine levels on the cytotoxicity of helenanolide type sesquiterpene lactones against KB cells. Bioorg. Med. Chem., 2001, 9, 2189-2194.
79. Fardella, G.; Barbetti, P.; Grandolini, G.; Chiappini, I.; Ambrogi, V.; Scarcia, V.; Furlani Candiani, A. Phenylthio-Derivatives of κ-Methylene-Δ-lactones as Prodrugs of Cytotoxic Agents. Eur. J. Med. Chem., 1999, 34, 515-523.
80. Fox, B. M.; Vroman, J. A.; Fanwick, P. E.; Cushman, M. Preparation and evaluation of sulfide derivatives of the antibiotic brefeldin a as potential prodrug candidates with enhanced aqueous solubilities. J. Med. Chem., 2001, 44, 3915-3924.
81. Ishihara, S.; Rumi, M.A.; Okuyama, T.; Kinoshita, Y. Effect of prostaglandins on the regulation of tumor growth. Curr. Med. Chem. Anticancer Agents, 2004, 4, 379-387.
82. Surh, Y.J.; Na, H.K.; Park, J.M.; Lee, H.N.; Kim, W.; Yoon, I.S.; Kim, D.D. 15-Deoxy-Δ κ-prostaglandin J, an electrophilic lipid mediator of anti-inflammatory and pro-resolving signaling. Biochem. Pharmacol., 2011, 82, 1335-1351.
83. Suzuki, M.; Morin, M.; Niwa, T.; Hirata, R.; Furuta, K.; Ishikawa, T.; Noyori, R. Chemical Implications for Antitumor and Antiviral Prostaglandins:_Reaction of_7-Prostaglandin A1 and Prostaglandin A1 Methyl Esters with Thiols. J. Am. Chem. Soc., 1997, 119, 2376-2385.
84. Bickley, J. F.; Ciucci, A.; Evans, P.; Roberts, S. M.; Ross, N.; Santoro, M. G. Reactions of some cyclopentenones with selected cysteine derivatives and biological activities of the product thioethers. Bioorg. Med. Chem., 2004, 12 3221-3227.
85. Ploemen, J. H. T. M.; Van Schanke, A.; Van Ommen, B.; Van Bladeren, P. J. Reversible conjugation of ethacrynic acid with glutathione and human glutathione S-transferase P1-1. Cancer Res., 1994, 54, 915-919.
86. Arnold, J. J.; Choksi, Y.; Chen, X.; Shimazaki, A.; Hatten, J.; Toone, E. J.; Epstein, D. L.; Challa, P. Eyedrops Containing SA9000 Prodrugs Result in Sustained Reductions in Intraocular Pressure in Rabbits. J. Ocul. Pharmacol. Ther., 2009, 25, 179-186.
87. Shi, B.; Greaney, M. F. Reversible Michael addition of thiols as a new tool for dynamic combinatorial chemistry. Chem. Commun., 2005, (7), 886-888
88. Sporn, M.B.; Liby, K.T.; Yore, M.M.; Fu, L.; Lopchuk, J.M.; Gribble, G.W. New Synthetic Triterpenoids: Potent Agents for Prevention and Treatment of Tissue Injury Caused by Inflammatory and Oxidative Stress. J. Nat. Prod., 2011, 74, 37-45.
89. Honda, T.; Rounds, B. V.; Gribble, G. W.; Suh, N.; Wang, Y.; Sporn, M. B. Design and Synthesis of 2-Cyano-3,12-dioxoolean-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.
90. Hong, D.S.; Kurzrock, R.; Supko, J. G.; Lawrence, D.P.; Wheler, J.J.; Meyer, C.J.; Mier, J.W.; Andreeff, M.; Shapiro, G.I.; Dezube B.J.; Phase I trial with a novel oral NF-ΔB/STAT3 inhibitor RTA 402 in patients with solid tumors and lymphoid malignancies. J. Clin. Oncol., 2008, 26, suppl; abstr 3517.
91. 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.
92. Ahmad, R.; Raina, D.; Meyer, C.; Kharbanda, S.; Donald Kufe, D. Triterpenoid CDDO-Me Blocks the NF-ΔB Pathway by Direct Inhibition of IKK on Cys-179. J. Biol Chem., 2006, 281, 35764-35769.
93. Ahmad, R.; Raina, D.; Meyer, C.; Donald 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.
94. Yore, M.M.; Kettenbach, A.N.; Sporn, M.B.; Gerber, S.A.; Liby, K.T. Proteomic Analysis Shows Synthetic Oleanane Triterpenoid Binds to mTOR. PLoS ONE, 2011, 6, e22862
95. Dinkova-Kostova, A. T.; Talalay, P.; Sharkey, J.; Zhang, Y.; Holtzclaw, 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.
96. Singh, S.; Aggarwal, BB.; Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane). J. Biol. Chem., 1995, 270, 24995-5000.
97. Anand, P.; Sung, B.; Kunnumakkara, A.B.; Rajasekharan, K.N.; Aggarwal, B.B. Suppression of pro-inflammatory and proliferative pathways by diferuloylmethane (curcumin) and its analogs dibenzoylmethane, dibenzoylpropane, and dibenzylideneacetone: Role of Michael acceptors and Michael donors. Biochem. Pharmacol., 2011, 82, 1901-1909.
98. Sun, A.; Lu, Y. J.; Hu, H.; Shoji, M.; Liotta, D. C.; Snyder, J. P. Curcumin analog cytotoxicity against breast cancer cells: exploitation of a redox-dependent mechanism. Bioorg. Med. Chem. Lett., 2009, 19, 6627-6631.
99. Wipf, P.; Halter Robert, J. Chemistry and Biology of Wortmannin. Org. Biomol. Chem., 2005, 3, 2053-2061.
100. Powis, G.; Bonjouklian, R.; Berggren, M. M.; Gallegos, A.; Abraham, R.; Ashendel, C.; Zalkow, L.; Matter, W. F.; Dodge, J.; Grindey, G.; Vlahos, C. J. Wortmannin, a Potent and Selective Inhibitor of Phosphatidylinositol-3-kinase. Cancer Res., 1994, 54, 2419-2423.
101. Yuan, H.; Barnes, K. R.; Weissleder, R.; Cantley, L.; Josephson, L. Covalent reactions of wortmannin under physiological conditions. Chem. Biol., 2007, 14, 321-328.
102. Blois, J.; Yuan, H.; Smith, A.; Pacold, M. E.; Weissleder, R.; Cantley, L. C.; Josephson, L. Slow self-activation enhances the potency of viridin prodrugs. J. Med. Chem., 2008, 51, 4699-4707.
103. Avonto, C.; Taglialatela-Scafati, O.; Pollastro, F.; Minassi, A.; Di Marzo, V.; De Petrocellis, L.; Appendino, G. An NMR Spectroscopic Method to Identify and Classify Thiol-Trapping Agents: Revival of Michael Acceptors for Drug Discovery? Angew. Chem. Int. Ed., 2010, 49, 1-6.
104. Cusack, K. P.; Arnold, L. D.; Barberis, C. E.; Chen, H.; Ericsson, A. M.; Gaza-Bulseco, G. S.; Gordon, T. D.; Grinell, C. M.; Harsch, A.; Pellegrini, M.; Tarcsa, E. A 13C NMR approach to categorizing potential limitations of alpha, beta-unsaturated carbonyl systems in drug-like molecules. Bioorg Med Chem Lett., 2004, 14, 5503-5508.
105. Dinkova-Kostova, A. T.; Massiah, M. A.; Bozak, R. E.; Hicks, R. J.; Talalay, P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc. Natl. Acad. Sci. U.S.A., 2001, 98 3404-3409.
106. Raj, L.; Ide, T.; Gurkar, A.U.; Foley, M.; Schenone, M.; Li, X.; Tolliday, N.J.; Golub, T.R.; Carr, S.A.; Shamji, A.F.; Stern, A.M.; Mandinova, A.; Schreiber, S.L.; Lee, S.W. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature, 2011, 475, 231-234.
107. Serafimova, I.M.; Pufall, M.A.; Krishnan, S.; Duda, K.; Cohen, M.S.; Maglathlin, R.L.; McFarland, J.M.; Miller, R.M.; Frödin, M.; Taunton J. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat. Chem. Biol., 2012, 8, 471-476.