Summary
Formation constants for the calcium(II), magnesium(II) and zinc(II) complexes of the orally effective iron chelator, pyridoxal isonicotinoyl hydrazone (PIH) and three analogues, pyridoxal benzoyl hydrazone (PBH), pyridoxalp-methoxybenzoyl hydrazone (PpMBH) and pyridoxalm-fluorobenzoyl hydrazone (PmFBH) have been determined by potentiometry at 25\dg C andI=0.1 M [KNO3]. The four ligands bind calcium(II) weakly and magnesium(II) only slightly more strongly, as a l: l complex which is formed at pH \s> 8. The chelation of zinc(II) for all the ligands studied was greater than that for calcium(II) and magnesium(II), with complexation generally becoming significant at about pH 5. Thus, chelation of zinc(II) but not calcium(II) or magnesium(II) at physiological pH, 7.4 may be expected. Calculated values of the concentration of uncomplexed metal ion indicate that the selectivity of these ligands towards Fe(III) is comparable to that of the clinically used chelator desferrioxamine.
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Avramovici-Grisaru S, Sarel S, Link G Hershko C (1983) Synthesis of iron bis(pyridoxal isonicotinoyl hydrazone)3 and the in vivo iron-removal properties of some pyridoxal derivatives. J Med Chem 26:298–302
Baker E, Vitolo ML, Webb J (1985) Iron chelation by pyridoxal isonicotinoyl hydrazone and analogues in hepatocytes in culture. Biochem Pharmacol 34:3011–3017
Cikrt M, Ponka P, Necas E, Neuwirt J (1980) Biliary iron excretion in rats following pyridoxal isonicotinoyl hydrazone. Br J Haematol 45:275–283
Herschko C, Avramovici-Grisaru S, Link G, Gelf L, Sarel S (1981) Mechanism of in vivo iron chelation by pyridoxal isonicotinoyl hydrazone and other imino derivatives of pyridoxal. J Lab Clin Med 98:99–108
Hoy T, Humphrys J, Jacobs A, Williams A, Ponka P (1979) Effective iron chelation following oral administration of an isoniazed-pyridoxal hydrazone. Br J Haematol 43:443–449
Irving H, Williams RJP (1948) Order of stability of metal complexes. Nature 162:746–747
Johnson DK, Pippard MJ, Murphy TB, Rose NJ (1982) An in vivo evaluation of iron-chelating drugs derived from pyridoxal and its analogs. J Pharmacol Exp Ther 221:399–403
Kim B-K, Heubers HA, Finch CA (1987) Effectiveness of oral iron chelators assayed in the rat. Am J Hematol 24:277–284
Martell AE, French-Anderson W, Badman DG (eds) (1981) Development of iron chelators for clinical use. Elsevier-North Holland, New York
Martell AE, Smith RM (1977) Critical stability constants, vol. 3, Plenum Press, New York
May PM, Bulman RA (1983) The present status of chelating agents in medicine. Prog Med Chem 20:225–336
May PM, Murray K, Williams DR (1985) The use of glass electrodes for the determination of formation constants-II. Simulation of titration data. Talanta 32:483–489
Modell B, Berdoukas V (1984) The clinical approach to thalassemia. Grune and Stratton, New York
Murray K, May PM (1984) Equilibrium simulation and titration analysis users manual. University of Wales Institute of Science and Technology, Cardiff CFI 3XF, UK
Ponka P, Borova J, Neuwirt J, Fuchs O (1979a) Mobilization of iron from reticulocytes. Identification of pyridoxal isonicotinoyl hydrazone as a new iron chelating agent. FEBS Lett 97:317–321
Ponka P, Borova J, Neuwirt J, Fuchs O, Necas E (1979b) A study of intracellular iron metabolism using pyridoxal isonicotinoyl hydrazone and other synthetic chelating agents. Biochim Biophys Acta 586:278–297
Ponka P, Richardson DR, Baker E, Schulman HM, Edward J (1988) Effect of pyridoxal isonicotinoyl hydrazone and other hydrazones on iron release from macrophages, reticulocytes and hepatocytes. Biochim Biophys Acta 967:122–129
Richardson DR, Baker E, Wilairat P, Vitolo ML, Webb J (1988) Effect of pyridoxal isonicotinoyl hydrazone and analogs on iron metabolism in hepatocytes and macrophages in culture. Birth Defects Orig Art Ser 23:81–88
Richardson DR, Wis Vitolo ML, Baker E, Webb J (1989a) Pyridoxal isonicotinoyl hydrazone and analogues: Study of their stability in acidic, neutral and basic aqueous solutions by ultraviolet/visible spectrophotometry. Biol Metals 2:69–76
Richardson DR, Wis Vitolo ML, Hefter GT, May PM, Clare BW, Webb J (1989b) Iron chelators of the pyridoxal isonicotinoyl hydrazone class: Part 1. Ionization characteristics of the ligands and their relevance to biological properties. Inorg Chim Acta (in press)
Webb J, Wis Vitolo ML (1988) Pyridoxal isonicotinoyl hydrazone (PIH): a promising new iron chelator. Birth Defects Orig Art Ser 23:63–70
Williams A, Hoy T, Pugh A, Jacobs A (1982) Pyridoxal complexes as potential chelating agents for oral therapy in transfusional iron overload. J Pharm Pharmacol 34:730–732
Wis Vitolo ML, Webb J, Saltman P (1984) Release of iron from ferritin by pyridoxal isonicotinoyl hydrazone and related compounds. J Inorg Biochem 20:255–262
Wis Vitolo ML, Hefter GT, Clare BW, Webb J (1989) Iron chelators of the pyridoxal isonicotinoyl hydrazone class: Part II. Formation constants with iron(III) and iron(II). Inorg Chim Acta (in press)
Yatsimirskii KB, Vasilév VP (1984) Instability constants of complex compounds. Pergamon, Elmsford NY
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Richardson, D.R., Hefter, G.T., May, P.M. et al. Iron chelators of the pyridoxal isonicotinoyl hydrazone class. Biol Metals 2, 161–167 (1989). https://doi.org/10.1007/BF01142555
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DOI: https://doi.org/10.1007/BF01142555