Spiro- and dispiro-1,2-dioxolanes: Contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides

Journal of Medicinal Chemistry

Volumn 50, Issue 23, 2007, Pages 5840-5847

  Wang, Xiaofang ^a   Dong, Yuxiang ^a   Wittlin, Sergio ^b   Creek, Darren ^c   Chollet, Jacques ^b   Charman, Susan A ^c   Tomas, Josefina Santo ^b   Scheurer, Christian ^b   Snyder, Christopher ^b   Vennerstrom, Jonathan L ^a  

^a NEBRASKA MEDICAL CENTER   (United States)

^b SWISS TROPICAL AND PUBLIC HEALTH INSTITUTE   (Switzerland)

^c MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 TRIOXOLANE; 1,3 DIOXOLANE DERIVATIVE; 3 PHENYL 14,15 DIOXADISPIRO[5.1.5.2]PENTADECANE; ALKENE; ARTEMISININ; CARBENOID; CARBON; DISPIRO 1,2 DIOXOLANE; IRON; OXYGEN; SPIRO 1,2 DIOXOLANE; SPIRO COMPOUND; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIMALARIAL ACTIVITY; ARTICLE; ATOM; BETA SCISSION REACTION; CARBON NUCLEAR MAGNETIC RESONANCE; CHEMICAL REACTION; COMPLEX FORMATION; CONTROLLED STUDY; DRUG POTENCY; DRUG SYNTHESIS; ELECTRON TRANSPORT; MOUSE; NONHUMAN; OZONOLYSIS; PARASITOSIS; PROTON NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; REDUCTION;

ANIMALS; ANTIMALARIALS; DIOXOLANES; DRUG RESISTANCE; FERROUS COMPOUNDS; MALARIA; MICE; OXIDATION-REDUCTION; PEROXIDES; PLASMODIUM BERGHEI; PLASMODIUM FALCIPARUM; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 36148961564     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0707673     Document Type: Article

References (43)

1. Bray, P. G.; Ward, S. A.; O'Neill, P. M. Quinolines and Artemisinin: Chemistry, Biology and History. Curr. Top. Microbiol. Immunol. 2005, 295, 3-38.
2. Winstanley, P.; Ward, S. Malaria Chemotherapy. Adv. Parasitol. 2006, 61, 47-76.
3. Tang, Y.; Dong, Y.; Vennerstrom, J. L. Synthetic Peroxides as Antimalarials. Med. Res. Rev. 2004, 24, 425-448.
4. Dong, Y.; Chollet, J.; Matile, H.; Charman, S. A.; Chiu, F. C. K.; Charman, W. N.; Scorneaux, B.; Urwyler, H.; Santo, Tomas, J.; Scheurer, C.; Snyder, C.; Dorn, A.; Wang, X.; Karle, J. M.; Tang; Y.; Wittlin, S.; Brun, R.; Vennerstrom, J. L. Spiro and Dispiro-1,2,4-Trioxolanes as Antimalarial Peroxides: Charting a Workable SAR Using Simple Prototypes. J. Med. Chem. 2005, 48, 4953-4961.
5. Tang, Y.; Dong, Y.; Wang, X.; Sriraghavan, K.; Wood, J. K.; Vennerstrom, J. L. Dispiro-1,2,4-trioxane Analogs of a Prototype Dispiro-1,2,4-trioxolane: Mechanistic Comparators for Artemisinin in the Context of Reaction Pathways with Iron(II). J. Org. Chem. 2005, 70, 5103-5110.
6. Creek, D. J.; Charman, W. N.; Chiu, F. C. K.; Prankerd, R. J.; McCullough, K. J.; Dong, Y.; Vennerstrom, J. L.; Charman, S. A. Iron Mediated Degradation Kinetics of Substituted Dispiro-1,2,4-Trioxolane Antimalarials. J. Pharm. Sci. 2007, 96, 2945-2956.
7. Griesbaum, K.; Krieger-Beck, P.; Beck, J. Dispiro-1,2,4-trioxlane durch Ozonolyse von Cycloalkylidencycloalkanen auf Polyethylen (Dispiro-1,2,4- trioxolane by Ozonolysis of Cycloalkylidenecycloalkanes on Polyethylene). Chem. Ber. 1991, 124, 391-396.
8. Perry, C. S.; Charman, S. A.; Prankerd, R. J.; Chiu, F. C. K.; Dong, Y.; Vennerstrom, J. L.; Charman, W. N. Chemical Kinetics and Aqueous Degradation Pathways of a New Class of Synthetic Ozonide Antimalarials. J. Pharm. Sci. 2006, 95, 737-747.
9. Tang, Y.; Dong, Y.; Karle, J. M.; DiTusa, C. A.; Vennerstrom, J. L. Synthesis of Tetrasubstituted Ozonides by the Griesbaum Coozonolysis Reaction: Diastereoselectivity and Functional Group Transformations by Post-Ozonolysis Reactions. J. Org. Chem. 2004, 69, 6470-6473.
10. Yoshida, M.; Miura, M.; Nojima, M.; Kusabayashi, S. Synthesis and Decomposition of E- and Z-3,3,5-Trisubstituted 1,2-Dioxolanes. J. Am. Chem. Soc. 1983, 105, 6279-6285.
11. Dussault, P. H.; Lee, H.-J.; Liu, X. Selectivity in Lewis Acid-Mediated Fragmentations of Peroxides and Ozonides: Application to the Synthesis of Alkenes, Homoallyl Ethers, and 1,2-Dioxolanes. J. Chem. Soc., Perkin Trans. 1 2000, 3006-3013.
12. Dussault, P. H.; Lee, I. Q.; Lee, H.-J.; Lee, R. L.; Niu, Q. J.; Schultz, J. A.; Zope U. R. Peroxycarbenium-Mediated C-C Bond Formation: Applications to the Synthesis of Hydroperoxides and Peroxides. J. Org. Chem. 2000, 65, 8407-8414.
13. Dussault, P. H.; Zope, U. Hydroperoxide-Mediated C-C Bond Formation: Synthesis of 1,2-Dioxolanes from Alkoxyhydroperoxides in the Presence of Lewis Acids. Tetrahedron Lett. 1995, 36, 3655-3658.
14. Ramirez, A.; Woerpel, K. A. Synthesis of 1,2-Dioxolanes by Annulation Reactions of Peroxycarbenium Ions with Alkenes. Org. Lett. 2005, 7, 4617-4620.
15. Dong, Y.; Matile, H.; Chollet, J.; Kaminsky, R.; Wood, J. K.; Vennerstrom, J. L. Synthesis and Antimalarial Activity of Eleven Dispiro-1,2,4,5-tetraoxane Analogs of WR 148999. 7,8,15,16-Tetraoxadispiro[5.2. 5.2]hexadecanes Substituted at the 1 and 10 Positions with Unsaturated and Polar Functional Groups. J. Med. Chem. 1999, 42, 1477-1480.
16. (a) Dong, Y.; Tang, T; Chollet, J.; Matile, H.; Wittlin, S.; Charman, S. A.; Charman, W. N.; Santo Tomas, J.; Scheurer, C.; Snyder, C.; Scorneaux, B.; Bajpai, S.; Alexander, S. A.; Wang, X.; Padmanilayam, M.; Rao, C. S.; Brun, R.; Vennerstrom, J. L. Effect of Functional Group Polarity on the Antimalarial Activity of Spiro and Dispiro-1,2,4-Trioxolanes. Bioorg. Med. Chem. 2006, 14, 6368-6382.
17. (b) Padmanilayam, M.; Scorneaux, B.; Dong, Y.; Chollet, J.; Matile, H.; Charman, S. A.; Creek, D. J.; Charman, W. N.; Santo Tomas, J.; Scheurer, C.; Wittlin, S.; Brun, R.; Vennerstrom, J. L. Antimalarial Activity of N-Alkyl Amine, Carboxamide, Sulfonamide, and Urea Derivatives of a Dispiro-1,2,4-trioxolane Piperidine. Bioorg. Med. Chem. Lett. 2006, 16, 5542-5545.
18. Helesbeux, J. J.; Peyronnet, D.; Labaied, M.; Grellier, P.; Frappier, F.; Seraphin, D.; Richomme, P.; Duval, O. Synthesis and Antimalarial Activity of Some New 1,2-Dioxolane Derivatives. J. Enzyme Inhib. Med. Chem. 2002, 17, 431-437.
19. Rücker, G.; Walter, R. D.; Manns, D.; Mayer, R. Antimalarial Activity of Some Natural Peroxides. Planta Med. 1991, 57, 295-296.
20. (a) Jefford, C. W. Why Artemisinin and Certain Synthetic Peroxides Are Potent Antimalarials. Implications for the Mode of Action. Curr. Med. Chem. 2001, 8, 1803-1826.
21. (b) Wu, Y. How Might Qinghaosu (Artemisinin) and Related Compounds Kill the Intraerythrocytic Malaria Parasite? A Chemist's View. Acc. Chem. Res. 2002, 35, 255-259.
22. (c) Dong, Y.; Vennerstrom, J. L. Mechanisms of in Situ Activation for Peroxidic Antimalarials. Redox Rep. 2003, 8, 284-288.
23. (d) O'Neill, P. M.; Posner, G. H. A Medicinal Chemistry Perspective on Artemisinin and Related Endoperoxides. J. Med. Chem. 2004, 47, 2945-2964.
24. (e) Posner, G. H.; O'Neill, P. H. Knowledge of the Proposed Chemical Mechanism of Action and Cytochrome P450 Metabolism of Antimalarial Trioxanes Like Artemisinin Allows Rational Design of New Antimalarial Peroxides. Acc. Chem. Res. 2004, 37, 397-404.
25. (f) Jefford, C. W. New Developments in Synthetic Peroxidic Drugs as Artemisinin Mimics. Drug Discovery Today 2007, 12, 487-495.
26. Creek, D. J.; Chiu, F. C. K.; Prankerd, R. J.; Charman, S. A.; Charman, W. N. Kinetics of Iron-Mediated Artemisinin Degradation: Effect of Solvent Composition and Iron Salt. J. Pharm. Sci. 2005, 94, 1820-1829.
27. We also isolated a 6% yield of an inseparable mixture of olefinic dehydration products of diol 7 as evidenced by a broad peak at δ 5.5 in the proton NMR.
28. Jaquet, C.; Stohler, H. R.; Chollet, J.; Peters. W. Antimalarial Activity of the Bicyclic Peroxide Ro 42-1611 (Arteflene) in Experimental Models. Trop. Med. Parasitol. 1994, 45, 266-271.
29. Cazelles, J.; Robert, A.; Meunier, B. Characterization of the Main Radical and Products Resulting from a Reductive Activation of the Antimalarial Arteflene (Ro 42-1611). J. Org. Chem. 1999, 64, 6776-6781. In this study, reaction of arteflene with manganese(II)-tetraphenylporphyrin in the presence of the stable nitroxide 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) formed an adduct between 9 and TEMPO in 6% yield.
30. O'Neill, P. M.; Bishop, L. P. D.; Searle, N. L.; Maggs, J. L.; Storr, R. C.; Ward, S. A.; Park. B. K.; Mabbs, F. Biomimetic Fe(II)-Mediated Degradation of Arteflene (Ro-42-1611). The First EPR Spin-Trapping Evidence for the Previously Postulated Secondary Carbon-Centered Cyclohexyl Radical. J. Org. Chem. 2000, 65, 1578-1582.
31. O'Neill, P. M.; Bishop, L. P.; Searle, N. L.; Maggs, J. L.; Ward, S. A.; Bray, P. G.; Storr, R. C.; Park, B. K. The Biomimetic Iron-Mediated Degradation of Arteflene (Ro-42-1611), an Endoperoxide Antimalarial: Implications for the Mechanism of Antimalarial Activity. Tetrahedron Lett. 1997, 38, 4263-4266.
32. (a) Bloodworth, A. J.; Shah, A. Iron(II)-Mediated Rearrangement of 1,2,4-Trioxanes into 1,2-Diol Monoesters via 1,5-Hydrogen Transfer. Tetrahedron Lett. 1995, 36, 7551-7554.
33. (b) Bloodworth, A. J.; Hagen, T.; Johnson, K. A.; LeNoir, I.; Moussy, C. Versatility of the Cyclo-oxymercuriation Route to 1,2,4-Trioxanes. Tetrahedron Lett. 1997, 38, 635-638. In certain cases, reactions of 1,2,4-trioxanes with iron(II) can lead to 1,5-hydrogen atom transfer with the concomitant formation of ketyl radicals which lose iron(II) to form stable carbonyl reaction products devoid of antimalarial activity. Such 1,2,4-trioxanes have weak antimalarial activities.
34. (a) Haq, A.; Kerr, B.; McCullough, K. J. A Rapid Route to Medium to Large Ring Lactones via the Thermoloysis of Dispiro-1,2,4-trioxane Derivatives. J. Chem. Soc., Chem. Commun. 1993, 1076-1078.
35. (b) Kerr, B.; McCullough, K. J. Dispiro-1,2,4-trioxanes as Precursors of Medium Ring Lactones: Thermolysis of Indan-2-spiro-3′-(1′,2′, 4′-trioxane)-6′-spiro-1″-cyclohexane. J. Chem. Soc., Chem. Commun. 1985, 590-592.
36. McCullough, K. J.; Nojima, M. Recent Advances in the Chemistry of Cyclic Peroxides. Curr. Org. Chem. 2001, 5, 601-636.
37. Sekiguchi, A.; Ando, W. Direct Synthesis of Terminal Olefins from Ketones. Application of (Chloromethyl)trimethylsilane to a Wittig Reaction. J. Org. Chem. 1979, 44, 413-415.
38. 2· Groups in Cyclohexylmethyl Radicals. J. Am. Chem. Soc. 1988, 110, 7494-7499.
39. Barrett, A. G. M.; Betts, M. J.; Fenwick, A. Acyl and Sulfonyl Isocyanates in β-Lactam Synthesis. J. Org. Chem. 1985, 50, 169-175.
40. Terent'ev, A. O.; Kutkin, A. V.; Platonov, M. M.; Ogibin, Y. N.; Nikishin, G. I. A New Method for the Synthesis of Bishydroperoxides Based on a Reaction of Ketals with Hydrogen Peroxide Catalyzed by Boron Trifluoride Complexes. Tetrahedron Lett. 2003, 44, 7359-7363.
41. Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J. Iodine as a Catalyst for Efficient Conversion of Ketones to gem-Dihydroperoxides by Aqueous Hydrogen Peroxide. Org. Lett. 2006, 8, 2491-2494.
42. Kim, H.-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.; McCullough, K. J. Synthesis and Antimalarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes. J. Med. Chem. 2001, 44, 2357-2361.
43. Griesbaum, K.; Kim, W.-S.; Nakamura, N.; Mori, M.; Nojima, M.; Kusabayashil, S. Ozonolysis of Vinyl Ethers in Solution and on Polyethylene. J. Org. Chem. 1990, 55, 6153-6161.