New hexadentate ligands composed of 1-hydroxy-2(1H )-pyrimidinone, α,ω-diamine and 1,1,1-tris(carboxyethoxymethyl)ethane or tri(carboxybutyl)isocyanurate. Synthesis and characterization of their iron(III) complexes

Abstract

The successive coupling of 1-benzyloxy-2(1H )-pyrimidinone with α,ω-diamines, 1,1,1-tris(carboxyethoxymethyl)ethane or tri(carboxybutyl)isocyanurate, and final removal of the benzyl protecting group afforded new hexadentate ligands (TEPOHn or TCPOH). The UV/VIS spectroscopic analysis in aqueous solution indicated 1∶1 stoichiometric complexation of the hexadentate ligand with iron(III). The relative stability constants of iron(III) complexes of the hexadentate ligands were estimated to be log K 24.4–26.3 by the competitive reaction with EDTA, suggesting that the stability was affected by the methylene chain length. The standard redox potential E_1/2 of Fe(TEPO2) was measured to be –493 mV at apparent pH 8.0 in 50% aqueous DMF solution. This value was approximately 300 mV higher than that of the iron(III) complex of natural desferrioxamine B (DFB). Further, all synthetic hexadentate ligands effectively removed 3–6 times as much iron(III) from human transferrin as DFB even though the ratio of the synthetic ligand to transferrin was one-fifth that of DFB.

References

1. The Development of Iron Chelators for Clinical Use, eds. R. J. Bergeron and G. M. Brittenham, CRC Press, Boca Raton, FL, 1992.
2. A. L. Crumbliss, in Handbook of Microbial Iron Chelates, ed. G. Winkelmann, CRC Press, Boca Raton, FL, 1991, p. 177.
3. M. T. Ahmet, C. S. Frampton and J. Silver, J. Chem. Soc., Dalton Trans., 1988, 1159.
4. C. J. Carrano and K. N. Raymond, J. Am. Chem. Soc., 1979, 101, 5401.
5. Z. Hou, D. W. Whisenhunt, jun., J. Xu and K. N. Raymond, J. Am. Chem. Soc., 1994, 116, 840.
6. (a) R. C. Scarrow, D. L. White and K. N. Raymond, J. Am. Chem. Soc., 1985, 107, 6540; (b) R. C. Scarrow, P. E. Riley, K. Abu-Dari, D. L. White and K. N. Raymond, Inorg. Chem., 1985, 24, 954.
7. M. Streater, P. D. Taylor, R. C. Hider and J. Porter, J. Med. Chem., 1990, 33, 1749.
8. G. J. Kontoghiorghes, The Lancet, 1985, 817; D. M. Taylor and G. J. Kontoghiorghes, Inorg. Chim. Acta, 1986, 125, L38; B. Faller and H. Nick, J. Am. Chem. Soc., 1994, 116, 3860.
9. J. Ohkanda, T. Tokumitsu, K. Mitsuhashi and A. Katoh, Bull. Chem. Soc. Jpn., 1993, 66, 841.
10. J. Ohkanda and A. Katoh, J. Org. Chem., 1995, 60, 1583.
11. J. Ohkanda and A. Katoh, Tetrahedron, 1995, 51, 12995.
12. J. Ohkanda, J. Kamitani, T. Tokumitsu, T. Konakahara and A. Katoh, J. Org. Chem., 1997, 62, 3618.
13. A. Winston and D. Kirchner, Macromolecules, 1978, 11, 597.
14. G. Anderegg, F. L'Eplattenier and G. Schwarzenbach, Helv. Chim. Acta, 1963, 46, 1400, 1409.
15. A. E. Martell and R. M. Smith, Critical Stability Constants, Plenum, New York, 1974, vol. 1.
16. S. R. Cooper, J. V. McArdle and K. N. Raymond, Proc. Natl. Acad. Sci. USA, 1978, 75, 3551.
17. K. Shimizu, K. Nakayama and M. Akiyama, Bull. Chem. Soc. Jpn., 1986, 59, 2421; M. Akiyama, A. Katoh and T. Ogawa, J. Chem. Soc., Perkin Trans. 1, 1989, 1213.
18. W. R. Harris, P. K. Bail and M. M. Crowley, Inorg. Chem., 1992, 31, 2700.
19. G. W. Bates and M. R. Schlabach, J. Biol. Chem., 1973, 248, 3228.
20. S. A. Nguyen, A. Craig and K. N. Raymond, J. Am. Chem. Soc., 1993, 115, 6758.