Synthesis, physicochemical characterization, and biological evaluation of 2-(1'-hydroxyalkyl-3-hydroxypyridin-4-ones: Novel iron chelators with enhanced pFe3+ values

Journal of Medicinal Chemistry

Volumn 42, Issue 23, 1999, Pages 4814-4823

  Liu, Zu D ^a   Khodr, Hicham H ^a   Liu, Ding Y ^a   Lu, Shu L ^a   Hider, Robert C ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 ETHYL 2 (1' HYDROXYETHYL) 3 HYDROXYPYRIDIN 4 ONE; 1,6 DIMETHYL 2 (1' HYDROXYETHYL) 3 HYDROXYPYRIDIN 4 ONE; 3 HYDROXY 4 PYRIDONE DERIVATIVE; CHELATING AGENT; FERRIC ION; IRON 59; UNCLASSIFIED DRUG;

ANIMAL MODEL; ARTICLE; CHELATION; CHEMICAL STRUCTURE; CONTROLLED STUDY; DRUG SYNTHESIS; IRON CHELATION; ISOTOPE LABELING; NONHUMAN; PHYSICAL CHEMISTRY; PKA; RAT;

ANIMALS; BILE; FERRITINS; HYDROGEN-ION CONCENTRATION; IRON; IRON CHELATING AGENTS; LIGANDS; POTENTIOMETRY; PYRIDINES; RATS; SPECTROPHOTOMETRY, ULTRAVIOLET; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0032701242     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm991080o     Document Type: Article

References (23)

1. Brittenham, G.M. Disorders of iron metabolism: deficiency and overload. In Hematology: Basic Principles and Practice; Hoffman, R., Benz, E., Shattil, S., Furie, B., Cohen, H., Eds.; Churchill Livingstone: New York, 1991; pp 327-349.
2. Hershko, C.; Konijn A.M.; Link, G. Iron chelators for thalasaemia. Br. J. Haematol. 1998, 101, 399-406.
3. Tilbrook, G. S.; Hider, R.C. Iron Chelators for clinical use. In Metal Irons in Biological Systems. Vol. 36: Iron Transport and Storage in Microorganisms, Plants and Animals; Sigel, A., Sigel, H., Eds.; Marcel Dekker: New York, 1998; pp 691-730.
4. Brittenham, G. M. Development of iron-chelating agents for clinical use. Blood 1992, 80, 569-574.
5. Singh, S.; Epemolu, O.; Dobbin, P. S.; Tilbrook, G. S.; Ellis, B. L.; Damani, L. A.; Hider, R. C. Urinary metabolic profiles in man and rat of 1,2-dimethyl- and 1,2-diethyl substituted 3-hydroxypyridin-4-ones. Drug Metab. Dispos. 1992, 20, 256-261.
6. Porter, J. B.; Morgan, J.; Hoyes, K. P.; Burke, L. C.; Huehns, E. R.; Hider, R. C. Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice. Blood 1990, 76, 2389-2396.
7. Porter, J. B.; Abeysinghe, R. D.; Hoyes, K. P.; Barra, C.; Huehns, E. R.; Brooks, P. N.; Blackwell, M. P.; Araneta, M.; Brittenham, G.; Singh, S.; Dobbin, P.; Hider, R. C. Contrasting interspecies efficacy and toxicology of 1,2-diethyl-3-hydroxypyridin-4-one, CP94, relates to differing metabolism of the iron chelating site. Br. J. Haematol. 1993, 85, 159-168.
8. Bergeron, R.J.; Streiff, R.R.; Wiegand, J.; Luchetta, G.; Creary, E.A.; Peter, H.H. A comparison of the iron-clearing properties of 1,2-dimethyl-3-hydroxypyrid-4-one, 1,2-diethyl-3-hydroxypyrid-4-one, and Deferoxamine. Blood 1992, 79, 1882-1890.
9. Porter, J. B.; Singh, S.; Hayes, K P.; Epemolu, O.; Abeysinghe, R. D.; Hider, R. C. Lessons from preclinical and clinical studies with 1,2-diethyl-3-hydroxypyridin-4-one, CP94 and related compounds. Adv. Expt. Med. Biol. 1994, 356, 361-370.
10. Singh, S.; Choudhury, R.; Epemolu, R. O.; Hider, R. C. Metabolism and pharmacokinetics of 1-(2′-hydroxyethyl)- and 1-(3́-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-ones in the rat. Eur. J. Drug Metab. Pharmacokinet. 1996, 21, 33-41.
11. 59Fe-ferritin loaded rat model. Biochem. Pharmacol. 1999, 57, 559-566.
12. Dobbin, P. S.; Hider, R. C.; Hall, A. D.; Taylor, P. D.; Sarpong, P.; Porter, J. B.; Xiao, G.; van der Helm, D. Synthesis, physicochemical properties, and biological evaluation of N-substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential. J. Med. Chem. 1993, 36, 2448-2458.
13. Rai, B. L.; Dekhordi, L. S.; Khodr, H.; Jin, Y.; Liu, Z.; Hider, R. C. Synthesis, Physicochemical properties and evaluation of N-substituted-2-alkyl-3-hydroxy-4(1H)-pyridinones. J. Med. Chem. 1998, 41, 3347-3359.
14. Mitsunobu, O. The use of diethylazodicarboxylate and triphenylphosphine in synthesis and transformation of nature products. Synthesis 1981, 1, 1-28.
15. Pippard, M. J.; Johnson, D. K.; Finch, C. A. A rapid assay for evaluation of iron chelating agents in rats. Blood 1981, 58, 685-692.
16. 3+ values of iron(III) ligands with clinical potential. In Metal Ions in Biology and Medicine Volume 5; Collery, Ph., Brätter, P., Negretti de Brätter, V., Khassanova, L., Etienne, J.C., Eds.; John Libbey Eurotext: Paris, 1998; pp 51-55.
17. Hider, R. C.; Epemolu, O.; Singh, S.; Porter, J. B. Iron chelator design. In Progress in Iron Research; Hershko, C., Konijn, A. M., Aisen, P. M., Eds.; Plenium Press: New York, 1994; Vol. 356, pp 343-349.
18. Xu, J. D.; Kullgren, B.; Durbin, P. W.; Raymond, K. N. Specific sequestering agents for the actinides. 28: Synthesis and initial evaluation of multidentate 4-carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone ligands for in vivo plutonium(IV) chelation. J. Med. Chem. 1995, 38, 2606-2614.
19. Achmatowicz, Jr., O.; Bukowski, P.; Szechner, B.; Zwierzchowska, Z.; Zamojski, A. Synthesis of methyl 2,3-dideoxy-DL-alk-2-enopyranosides from furan compounds; A general approach to the total synthesis of monosaccharides. Tetrahedron 1971, 27, 1973-1996.
20. Tate, B. E.; Miller, R. L. U.S.A. Patent 3 130 204, 1964.
21. Ellis, B. L.; Duhme, A. K.; Hider, R. C.; Hossain, M. B.; Rizvi, S.; van der Helm, D. Synthesis, physicochemical properties, and biological evaluation of hydroxypyranones and hydroxypyridinones: Novel bidentate ligands for cell-labeling J. Med. Chem. 1996, 39, 3659-3670.
22. Taylor, P. D.; Morrison, I. E. G.; Hider, R. C. Microcomputer application of nonlinear regression analysis to metal-ligand equilibria. Talanta 1988, 35, 507-512.
23. Gran, G. Determination of the equivalence point in potentiometric titration. Analyst 1952, 77, 661-671.