The behaviour of qinghaosu (artemisinin) in the presence of heme iron(II) and (III)

Tetrahedron Letters

Volumn 37, Issue 2, 1996, Pages 253-256

  Haynes, Richard K ^a   Vonwiller, Simone C ^b  

^a HONG KONG UNIVERSITY OF SCIENCE AND TECHNOLOGY   (Hong Kong)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

ARTEMISININ;

ARTICLE; DRUG DEGRADATION; OXIDATION; REACTION ANALYSIS;

EID: 0030066679     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(95)02141-8     Document Type: Article

References (22)

1. Wellcome Trust Artemisinin Meeting: 1993, Trans Roy. Soc. Trop. Med. Hyg. 1994, 88, S1.
2. Vennerstrom, J. L.; Eaton, J. W. J. Med. Chem. 1988, 31, 1269.
3. Meshnick, S. R.; Thomas, A.; Ranz, A.; Xu, C.-M.; Pan, H.-Z. Mol. Biochem. Parasitol. 1991, 49, 181.
4. Hong, Y.-L.; Yang, Y.-Y.; Meshnick, S. R. Mol. Biochem. Parasitol. 1994, 63, 121.
5. Hunt, N. H.; Stocker, R. Blood Cells 1999, 16, 499.
6. Posner, G. H.; Oh, C. H.; Wang, D.; Gerena, L.; Milhous, W. K.; Meshnick, Asamahasadka, W. J. Med. Chem. 1994, 37, 1256. A proposal of β-scission in synthetic 1,2,4-trioxanes is based on incorrectly assigned products: Jefford, C. W.; Favarger, F.; Vicente, M. G. H.; Jacquier, Y. Helv. Chim. Acta 1995, 78, 452. We thank Professor J. Boukonvalas for most pertinent information.
7. Posner, G. H.; Oh, C. H.; Wang, D.; Gerena, L.; Milhous, W. K.; Meshnick, Asamahasadka, W. J. Med. Chem. 1994, 37, 1256. A proposal of β-scission in synthetic 1,2,4-trioxanes is based on incorrectly assigned products: Jefford, C. W.; Favarger, F.; Vicente, M. G. H.; Jacquier, Y. Helv. Chim. Acta 1995, 78, 452. We thank Professor J. Boukonvalas for most pertinent information.
8. Slater, A. F. G.; Swiggard, W. J.; Orton, B. R.; Flitter, W. D.; Goldberg, D. E.; Cerami, A.; Henderson, G. B. Proc. Natl. Acad. Sci. USA 1991, 88, 325; Dorn, A.; Stoffel, A.; Matile, H.; Bubendorf, A.; Ridley, R. G. Nature, 1995, 374, 269. The resting state for hemin is in the iron(III) state; formation of μ-oxo dimers from heme iron(II) and oxygen or peroxides is of course well known, but apparently unrecorded within the parasitized erythrocyte.
9. Slater, A. F. G.; Swiggard, W. J.; Orton, B. R.; Flitter, W. D.; Goldberg, D. E.; Cerami, A.; Henderson, G. B. Proc. Natl. Acad. Sci. USA 1991, 88, 325; Dorn, A.; Stoffel, A.; Matile, H.; Bubendorf, A.; Ridley, R. G. Nature, 1995, 374, 269. The resting state for hemin is in the iron(III) state; formation of μ-oxo dimers from heme iron(II) and oxygen or peroxides is of course well known, but apparently unrecorded within the parasitized erythrocyte.
10. 3), 2.87 (1H, dq, J = 6.7, 5.3 Hz, H9), *3.37 (1H, dq, J = 7.2, 5.3 Hz, H9).
11. 1H NMR spectroscopy of product mixtures calibrated against 1,3,5-trinitrobenzene.
12. Bayer, E.; Hill, H. A. O.; Röder, A.; Williams, R. J. P. J. Chem. Soc., Chem. Commun. 1969, 109.
13. See for example: Beckwith, A. L. J.; Wagner, R. D. J. Am. Chem. Soc. 1979, 101, 7099.
14. Prepared from qinghao acid: Vonwiller, S. C.; Warner, J. A.; Mann, S. T.; Haynes, R. K. J. Am. Chem. Soc. 1995, in press.
15. Posner, G. H.; Cumming, J. N.; Ploypradith, P.; Oh, C.-H. J. Am. Chem. Soc. 1995, 117, 5885.
16. cf. Posner, G. H.; Wang, D.; Cumming, J. N.; Oh, C. H.; French, A. N.; Bodley, A. L.; Shapiro, T. A. J. Med. Chem. 1995, 38, 2273.
17. Further commentary must await identification of the hemin-QHS adduct. The formation of 17 and hence of 11 may be irrelevant to biological activity of qinghaosu, as discussed in the following paper.
18. Traces of 11 (ca. 1-2%) occasionally form in our aqueous systems in the presence of cysteine.
19. Sawaki, Y.; Ogata, Y. J. Org. Chem. 1976, 41, 2340.
20. Van Rheenan, V. Tetrahedron Lett. 1969, 985; Barton, D. H. R.; Wozniak, J.; Zard, S. Z. Tetrahedron 1989, 45, 3741.
21. Van Rheenan, V. Tetrahedron Lett. 1969, 985; Barton, D. H. R.; Wozniak, J.; Zard, S. Z. Tetrahedron 1989, 45, 3741.
22. At pH 10, conditions under which nucleophilic ring opening of QHS by hydroxide is likely to occur to expose the free formyl group, 3 and 10 are formed in a 30:70 ratio from QHS in the presence of hemin; at pH 7.8, 3 is the only product.