Design, synthesis, derivatization, and structure-activity relationships of simplified, tricyclic, 1,2,4-trioxane alcohol analogues of the antimalarial artemisinin

Journal of Medicinal Chemistry

Volumn 41, Issue 6, 1998, Pages 952-964

  Gumming, Jared N ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,2,4 TRIOXANE DERIVATIVE; ANTIMALARIAL AGENT; ARTEMISININ DERIVATIVE;

ANTIMALARIAL ACTIVITY; ARTICLE; DRUG DESIGN; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TRANSFORMATION; NONHUMAN; PLASMODIUM FALCIPARUM; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTIMALARIALS; ARTEMISININS; CHLOROQUINE; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HETEROCYCLIC COMPOUNDS; PLASMODIUM FALCIPARUM; SESQUITERPENES; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032510380     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970711g     Document Type: Article

References (71)

1. Olliaro, P.; Cattani, J.; Wirth, D. Malaria, the Submerged Disease. J. Am. Med. Assoc. 1996, 275, 230-233.
2. Summarized in Tropical Disease Research: Progress 1975-94, Highlights 1993-94; Twelfth Programme Report of the UNDP/ World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDK); World Health Organization: Geneva, 1995; Chapter 4.
3. Steele, R. W.; Baffoe-Bonnie, B. Cerebral Malaria in Children. Pedia Cr. Infect. Dis. J. 1995, 14, 281-285.
4. Warrell, D. A. Cerebral Malaria. Schweiz. Med. Wschr. 1992, 722, 879-886.
5. Hoffman, S. L. Artemether in Severe Malaria-Still Too Many Deaths. N. Engl. J. Med. 1996, 335, 124-126.
6. Collins, F. H.; Paskewitz, S. M. Malaria: Current and Future Prospects for Control. Annu. Rev. Entomol. 1995, 40,195-219.
7. Overviewed in Klayman, D. L. Qinghaosu (Artemisinin): An Antimalarial Drug from China. Science 1985,228, 1049-1055.
8. Qinghaosu Antimalaria Coordinating Research Group. Antimalaria Studies on Qinghaosu. Chin. Med. J. 1979, 92, 811-816.
9. Hien, T. T.; White, N. J. Qinghaosu. Lancet 1993, 347, 603608.
10. Luo, X. D.; Shen, C. C. The Chemistry, Pharmacology, and Clinical Applications of Qinghaosu (Artemisinin) and its Derivatives. Med. Res. Rev. 1987, 7, 29-52.
11. White, N. J. Artemisinin: Current Status. Trans. R. Soc. Trop. Med. Hyg. 1994, 88, 3-4.
12. Phuong, C. X. T.; Bethell, D. B.; Phuong, P. T.; Mai, T. T. T.; Thuy, T. T. N.; Ha, N. T. T.; Thuy, P. T. T.; Anh, N. T. T.; Day, N. P. J.; White, N. J. Comparison of Artemisinin Suppositories, Intramuscular Artesunate, and Intravenous Quinine for Treatment of Severe Childhood Malaria. Trans. R. Soc. Trop. Med. Hyg. 1997, 91, 335-342.
13. Boele van Hensbroek, M.; Onyiorah, E.; Jaffar, S.; Schneider, G.; Palmer, A.; Frenkel, J.; Enwere, G.; Forck, S.; Nusmeijer, A.; Bennett, S.; Greenwood, B.; Kwiatkowski, D. A Trial of Artemether or Quinine in Children with Cerebral Malaria. N. Engl. J. Med. 1996, 335, 69-75.
14. Petras, J. M.; Kyle, D. E.; Gettayacamin, M.; Young, G. D.; Bauman, R. A.; Webster, H. K.; Corcoran, K. D.; Peggins, J. O.; Vane, M. A.; Brewer, T. G. Arteether: Risks of Two-Week Administration in Macaca mulatto. Am. J. Trop. Med. Hyg. 1997, 56, 390-396.
15. Artesunate Rectocaps: A Life-Saving Intervention. In TDK News; UNDP/World BankAVHO Special Programme for Research and Training in Tropical Diseases (TDK); World Health Organization: Geneva, 1997; pp 1-2.
16. Gumming, J. N.; Ploypradith, P.; Posner, G. H. Antimalarial Activity of Artemisinin (Qinghaosu) and Related Trioxanes: Mechanism of Action. Adv. Pharmacol. 1997, 37, 2253-297.
17. For a recent study of solvent and steric effects in iron(II) induced peroxide decompositions, see Barton, D. H. R.; Launay, F. The Selective Functionalization of Saturated Hydrocarbons. Part 40. Aspects of Fe11 Based Peroxide Fragmentation in Pyridine Solution. Tetrahedron 1997, 53, 14565-14578.
18. Edwards, G. Home-Mediated Decomposition of Artemisinin and Its Derivatives: Pharmacological and Toxicological Considerations. J. Pharm. Pharmacol. 1997, 49, 49-53.
19. Rosenthal, P. J.; Meshnick, S. R. Hemoglobin Catabolism and Iron Utilization by Malaria Parasites. Mol. Biochem. Parasitol. 1996, 83, 131-139.
20. Maeno, Y.; Toyoshima, T.; Fujioka, H.; Ito, Y.; Meshnick, S. R.; Benakis, A.; Milhous, W. K.; Aikawa, M. Morphological Effects of Artemisinin in Plasmodium falciparum. Am. J. Trop. Med. Hyg. 1993, 49, 485-491.
21. 3H]-Dihydroartemisinine in P. falciparum In Vitro. Ann. Trop. Med. Parasitol. 1985, 79, 367-374.
22. Meshnick, S. R.; Taylor, T. E.; Kamchonwongpaisan, S. Artemisinin and the Antimalarial Endoperoxides: From Herbal Remedy to Targeted Chemotherapy. Microbiol. Rev. 1996, 60, 301-315.
23. Haynes, R. K; Vonwiller, S. C. The Behaviour of Qinghaosu (Artemisinin) in the Presence of Heme Iron (II) and (III). Tetrahedron Lett. 1996, 37, 253-256.
24. Hong, Y. L.; Yang, Y. Z.; Meshnick, S. R. The Interaction of Artemisinin with Malaria Hemozoin. Mol. Biochem. Parasitol. 1994, 63, 121-128.
25. Robert, A.; Meunier, B. Characterization of the First Covalent Adduct Between Artemisinin and a Heme Model. J. Am. Chem. Soc. 1997, 119, 5968-5969.
26. Vroman, J. A.; Khan, I. A.; Avery, M. A. Copper(I) Catalyzed Conjugated Addition of Grignard Reagent to Acrylic Acids: Homologation of Artemisinic Acid and Subsequent Conversion to 9-Substituted Artemisinin Analogs. Tetrahedron Lett. 1997, 38, 6173-6176.
27. Lin, A. J.; Zikry, A. B.; Kyle, D. E. Antimalarial Activity of New Dihydroartemisinin Derivatives. 7.4-(p-Substituted phenyD-4(fl or S)-[10(α or β)-dihydroartemisininoxy]butyric Acids. J. Med. Chem. 1997, 40, 1396-1400.
28. Mekonnen, B.; Ziffer, H. A New Route to AT-Substituted 11Azaartemisinins. Tetrahedron Lett. 1997, 38, 731-734. . .
29. O'Neill, P. M.; Bishop, L. P.; Storr, R. C.; Hawley, S. R.; Maggs, J. L.; Ward, S. A.; Park, B. K. Mechanism-Based Design of Parasite-Targeted Artemisinin Derivatives: Synthesis and Antimalarial Activity of Benzylamino and Alkylamino Ether Analogues of Artemisinin. J. Med. Chem. 1996, 39, 4511-4514.
30. Jung, M. Current Developments in the Chemistry of Artemisinin and Related Compounds. Curr. Med. Chem. 1994, 1, 46-60.
31. Zaman, S. S.; Sharma, R. P. Some Aspects of the Chemistry and Biological Activity of Artemisinin and Related Antimalarials. Heterocycles 1991, 32, 1593-1638.
32. Singh, C.; Misra, D.; Saxena, G.; Chandra, S. In vivo Potent Antimalarial 1,2,4-Trioxanes: Synthesis and Activity of 8-(α-arylvinyl)-6,7,10-trioxaspiro[4,5]decanes and 3-(α-arylvinyl)-1,2,5-trioxaspiro[5,5]undecanes Against Plasmodium berghei in Mice. Bioorg. Med. Chem. Lett. 1995, 5, 1913-1916.
33. Jefford, C. W.; Kohmoto, S.; Jaggi, D.; Tirnari, G.; Rossier, G. C.; Rudaz, M.; Barbuzzi, O.; Gérard, D.; Burger, U.; Kamalaprija, P.; Mareda, J.; Bernardinelli, G.; Manzanares, I.; Canfield, C. J.; Fleck, S. L.; Robinson, B. L.; Peters, W. 51. Synthesis, Structure, and Antimalarial Activity of Some Enantiomerically Pure, cis-Fused Cyclopenteno-1,2,4-trioxanes. Helv. Chim. Acta 1995, 78, 647-662.
34. Posner, G. H.; Oh, C. H.; Gerena, L.; Milhous, W. K. Synthesis and Antimalarial Activities of Structurally Simplified 1,2,4Trioxanes Related to Artemisinin. Heteroatom Chem. 1995, 6, 105-116.
35. Posner, G. H.; Oh, C. H.; Gerena, L.; Milhous, W. K Extraordinarily Potent Antimalarial Compounds: New, Structurally Simple, Easily Synthesized, Tricyclic 1,2,4-Trioxanes. J. Med. Chem. 1992, 35, 2459-2467.
36. Fleck, S. L.; Robinson, B. L.; Peters, W. The Chemotherapy of Rodent Malaria. LIV. Combinations of 'Fenozan B07' (Fenozan50F), a Difluorinated 3,3'-Spirocyclopentane 1,2,4-Trioxane, with Other Drugs Against Drug-Sensitive and Drug-Resistant Parasites. Ann. Trop. Med. Parasitol. 1997, 91, 33-39.
37. Posner, G. H.; Oh, C. H.; Webster, K; Ager, A. L., Jr.; Rossan, R. N. New, Antimalarial, Tricyclic 1,2,4-Trioxanes: Preclinical Evaluation in Mice and Monkeys. Am. J. Trop. Med. Hyg. 1994, 50, 522-526.
38. Grigorov, M.; Weber, J.; Tronchet, J. M. J.; Jefford, C. W.; Milhous, W. K.; Marie, D. A QSAR Study of the Antimalarial Activity of Some Synthetic 1,2,4-Trioxanes. J. Chem. Inf. Cornput. Sci. 1997, 37, 124-130.
39. Avery, M. A.; Fan, P.; Karle, J. M.; Bonk, J. D.; Miller, R.; Coins, D. K. Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 3. Total Synthesis of (+)-13-Carbaartemisinin and Related Tetra- and Tricyclic Structures. J. Med. Chem. 1996, 39, 1885-1897.
40. 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 IronMediated Degradation of Arteflene (Ro-42-1611), an Endoperoxide Antimalarial: Implications for the Mechanism of Antimalarial Activity. Tetrahedron Lett. 1997, 38, 4263-4266.
41. Posner, G. H.; Wang, D.; Gumming, J. N.; Oh, C. H.; French, A. N.; Bodley, A. L.; Shapiro, T. A. Further Evidence Supporting the Importance of and Restrictions on a Carbon-Centered Radical for High Antimalarial Activity of 1,2,4-Trioxanes Like Artemisinin. J. Med. Chem. 1995, 38, 2273-2275.
42. Jefford, C. W.; Favarger, F.; Vicente, M. H.; Jacquier, Y. 35. The Decomposition of cis-Fused Cyclopenteno-1,2,4-trioxanes Induced by Ferrous Salts and Some Oxophilic Reagents. Helv. Chim. Acta 1995, 78, 452-458.
43. For a proposal of an ionic mechanism, see: Haynes, R. K.; Vonwiller, S. C. The Behaviour of Qinghaosu (Artemisinin) in the Presence of Non-Heme Iron(II) and (III). Tetrahedron Lett. 1996, 37, 257-260.
44. Posner, G. H.; Park, S. B.; Gonzalez, L.; Wang, D.; dimming, J. N.; Klinedinst, D.; Shapiro, T. A.; Bachi, M. D. Evidence for the Importance of High-Valent Fe=O and of a Diketone in the Molecular Mechanism of Action of Antimalarial Trioxane Analogues of Artemisinin. J. Am. Chem. Soc. 1996, 118, 3537-3538.
45. Jefford, C. W.; Velarde, J. A.; Bernardinelli, G.; Bray, D. H.; Warhurst, D. C.; Milhous, W. K. 198. Synthesis, Structure, and Antimalarial Activity of Tricyclic 1,2,4-Trioxanes Related to Artemisinin. Helv. Chim. Acta 1993, 76, 2775-2788.
46. Oh, C. H.; Wang, D.; Cumming, J. N.; Posner, G. H. Antimalarial 1,2,4-Trioxanes Related to Artemisinin: Rules for Assignment of Relative Stereochemistry in Diversely Substituted Analogs. Spectrosc. Lett. 1997, 30, 241-255.
47. Posner, G. H.; Oh, C. H.; Wang, D.; Gerena, L.; Milhous, W. K; Meshnick, S. R.; Asawamahasakda, W. Mechanism-Based Design, Synthesis, and in Vitro Antimalarial Testing of New 4-Methylated Trioxanes Structurally Related to Artemisinin: The Importance of a Carbon-Centered Radical for Antimalarial Activity. J. Med. Chem. 1994, 37, 1256-1258.
48. C4-Phenyltrioxanes were synthesized starting with condensation of the pyrrolidino enamine of cyclohexanone with a-phenyl acrylonitrile. For complete details, see Oh, C. H.; Posner, G. H. Syntheses and Iron(II) Induced Reactions of Phenyl-Substituted 1,2,4-Trioxanes. Bull. Korean Chem. Soc. 1997, 18, 644-648.
49. At some point after the work described herein, 2-(2'-cyanoethyl)cyclohexanone (13) became no longer commonly commercially available.
50. Reitz, A. B.; Nortey, S. O.; Jordan, A. D., Jr.; Mutter, M. S.; Maryanoff, B. E. Dramatic Concentration Dependence of Stereochemistry in the Wittig Reaction. Examination of the Lithium Salt Effect. J. Org. Chem. 1986, 51, 3302-3308.
51. Johnson, A. W. Ylides and Imines of Phosphorus; John Wiley: New York, 1993; Chapter 8.1.5.
52. Tidwell, T. T. Oxidation of Alcohols by Activated Dimethyl Sulfoxide and Related Reactions: An Update. Synthesis 1990, 857-870.
53. Mancuso, A. J.; Swern, D. Activated Dimethyl Sulfoxide: Useful Reagents for Synthesis. Synthesis 1981, 165-185.
54. 4β(hydroxymethyl)trioxane 5b, see: Posner, G. H.; Ploypradith, P.; Hapangama, W.; Wang, D.; Gumming, J. N.; Dolan, P.; Kensler, T. W.; Klinedinst, D.; Shapiro, T. A.; Zheng, Q. Y.; Murray, C. K.; Pilkington, L. G.; Jayasinghe, L. R.; Bray, J. F.; Daughenbaugh, R. Trioxane Dimers Have Potent Antimalarial, Antiproliferative and Antitumor Activities In Vitro. Bioorg. Med. Chem. 1997, 5, 1257-1265.
55. Richardson, D. P.; Carr, P. W.; Gumming, J. N.; Harbison, W. G.; Raoof, N. D.; Sanders, M. S.; Shin, E.; Smith, T. E.; Wintner, T. H. Stereoselective Synthesis of 7R-Paeonimetaboline-L; Stereoselective Route Towards Paeoniflorigenone. Tetrahedron Lett. 1997, 38, 3817-3820.
56. McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. C. A Convenient Procedure for the Monosilylation of Symmetric l,nDiols. J. Org. Chem. 1986, 51, 3388-3390.
57. LeFevre, G. N.; Crawford, R. J. Intramolecular Steric Factors in the Thermolysis of 4-Alkylidene-l-pyrazolines. J. Am. Chem. Soc. 1986, 108, 1019-1027.
58. Corey, E. J.; Kim, C. U.; Takeda, M. A Method for Selective Conversion of Allylic and Benzylic Alcohols to Halides Under Neutral Conditions. Tetrahedron Lett. 1972,13, 4339-4342.
59. For example, see Hart, D. J.; Hong, W. P.; Hsu, L. Y. Total Synthesis of (±)-Lythrancepine II and (±)-Lythrancepine III. J. Org. Chem. 1987, 52, 4665-4673.
60. Posner, G. H.; Gumming, J. N.; Ploypradith, P.; Oh, C. H. Evidence for Fe(IV)=O in the Molecular Mechanism of Action of the Trioxane Antimalarial Artemisinin. J. Am. Chem. Soc. 1995,117, 5885-5886.
61. CRC Handbook of Chemistry and Physics, 76th ed.; Lide, D. R.; Frederikse, H. P. R., Eds.; CRC Press: Boca Raton, FL, 1995; 9-73.
62. Auner, N.; Walsh, R.; Westrup, J. Kinetic Determination of the Bond Dissociation Energy D(Me3SiCMe2CH2-H) and the Magnitude of the Stabilization Energy in a β-Silicon-substituted Alkyl Radical. J. Chem. Soc., Chem. Commun. 1986, 207-208.
63. For an overview of olefin forming β-elimination reactions, see Motherwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis; Academic Press: San Diego, 1992; Chapter 4.
64. Ponnudurai, T.; Leeuwenberg, A. D. E. M.; Meuwissen, J. H. E. T. Chloroquine Sensitivity of Isolates of Plasmodium falciparum Adapted to In Vitro Culture. Trop. Geogr. Med. 1981, 33, 50-54.
65. Desjardins, R. E.; Canfield, C. J.; Haynes, J. D.; Chulay, J. D. Quantitative Assessment of Antimalarial Activity In Vitro by a Semiautomated Microdilution Technique. Antimicrob. Agents Chemother. 1979, 16, 710-718.
66. Milhous, W. K; Weatherly, N. F.; Bowdre, J. H.; Desjardins, R. E. In Vitro Activities of and Mechanisms of Resistance to Antifol Antimalarial Drugs. Antimicrob. Agents Chemother. 1985, 27, 525-530.
67. For experimental .details of the testing protocol, including references to development of the assay, see Posner, G. H.; Gonzalez, L.; Gumming, J. N.; Klinedinst, D.; Shapiro, T. A. Synthesis and Antimalarial Activity of Heteroatom-Containing Bicyclic Endoperoxides. Tetrahedron 1997, 53, 37-50.
68. Posner, G. H.; McGarvey, D. J.; Oh, C. H.; Kumar, N.; Meshnick, S. R.; Asawamahasakda, W. Structure-Activity Relationships of Lactone Ring-Opened Analogs of the Antimalarial 1,2,4Trioxane Artemisinin. J. Med. Chem. 1995,38, 607-612.
69. For a description of the testing protocol, see Kumar, N.; Zheng, H. Stage-specific Gametocytocidal Effect In Vitro of the Antimalaria Drug Qinghaosu on Plasmodium faldparum. Parasitai. Res. 1990, 76, 214-218.
70. Coleman, R.; Nath, A. K.; Schneider, I.; Song, G. H.; Klein, T. A.; Milhous, W. K. Prevention of Sporogony of Plasmodium faldparum and P. berghei in Anopheles stephensi Mosquitos by Transmission-blocking Antimalarials. Am. J. Trop. Med. Hyg. 1994, 50, 646-653.
71. We have deposited the atomic coordinates for ester 12 with the Cambridge Crystallographic Data Center. The coordinates can be obtained, on request, from the Director, Cambridge Crystallographic Data Center, 12 Union Road, Cambridge, CB2 1EZ, U.K.