Галерея 3372890

Галерея 3372890
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Dalton Trans. Author manuscript; available in PMC 2012 Jun 12.
Find articles by Christian R. Kowol
a Department of Inorganic and Analytical Chemistry, University of Szeged, P.O. Box 440, H-6701, Szeged, Hungary. mehc@ydeyne . u-szeged.hu; Fax: +36 62 420505

b University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090, Vienna, Austria

c Bioinorganic Chemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, P.O. Box 440, Szeged, H-6701, Hungary

The publisher's final edited version of this article is available at Dalton Trans
GUID: 679A655D-318E-412E-A5B9-FD8F9FF8BF50
a Uncertainties (SD) are shown in parentheses for the TSCs studied in the present work.
d Determined by UV-vis spectrophotometry.
c For more data at various pH values see Fig. 11 and S8 in ESI. †
d It cannot be distinguished from the peak of ligand; at pH 3.6 ligand: λ EX = 315 nm, λ EM = 390 nm (I = 81), GaIII–TSC: λ EX = 315 nm, λ EM = 390 nm (I = 120).
e n.m. = Non measurable in the range of λ EX = 300–600 nm.
a Uncertainties (SD) are shown in parentheses for the complexes determined in the present work.
b Determined by pH-potentiometry; β (M p L q H r ) = [M p L q H r ]/[M] p [L] q [H] r ; p M + q L + r H ⇌ M p L q H r; for the detailed equilibria see
SI .
d Determined by UV-vis spectrophotometric measurements.
e pM = −log[Fe III ] at pH 7.40; c L / c M = 10; c M = 1 μM; pM = 26.5 for desferrioxamine B; 19.3 for deferiprone; 20.3 for human serum transferrin; 24.3 for DOTA taken from ref. 20 - 22 .
log K = logβ([ML 2 ]) − 2logβ(H 2 L + )
a Formal redox potential values of [Fe III L 2 ] + complexes vs . NHE at t = 25.0 °C, I = 0.10 mol dm −3 (KCl) in 30% (w/w) DMSO/H 2 O mixture at different pH; c (Fe III ) = 1 × 10 −3 mol dm −3 ; M:L = 1 : 2.
b Peak potential separation (Δ E = E a - E c ) (a: anode; c: cathode).
d Molar fraction of Fe calculated at c (Fe III ) = 1 × 10 −3 mol dm −3 ; M:L = 1 : 2.
1. West DX, Padhye SB, Sonawane PB. Struct. Bonding (Berlin) 1991; 76 :1. [ Google Scholar ]
2. Nutting CM, van Herpen CML, Miah AB, Bhide SA, Machiels JP, Buter J, Kelly C, de Raucourt D, Harrington KJ. Ann. Oncol. 2009; 20 :1275. [ PubMed ] [ Google Scholar ]
3. Richardson DR, Sharpe PC, Lovejoy DB, Senatatne D, Kalinowski DS, Islam M, Bernhardt PV. J. Med. Chem. 2006; 49 :6510. [ PubMed ] [ Google Scholar ]
4. Yu Y, Kalinowski DS, Kovacevic Z, Siafakas AR, Jansson PJ, Stefani C, Lovejoy DB, Sharpe PC, Bernhardt PV, Richardson DR. J. Med. Chem. 2009; 52 :5271. [ PubMed ] [ Google Scholar ]
5. Whitnall M, Howard J, Ponka P, Richardson DR. Proc. Natl. Acad. Sci. U. S. A. 2006; 103 :14901. [ PMC free article ] [ PubMed ] [ Google Scholar ]
6. Birch N, Wang X, Chong HS. Expert Opin. Ther. Pat. 2006; 16 :1533. [ Google Scholar ]
7. Shao J, Zhou B, Di Bilio AJ, Zhu L, Wang T, Shih CQJ, Yen Y. Mol. Cancer Ther. 2006; 5 :586. [ PubMed ] [ Google Scholar ]
8. Kowol CR, Trondl R, Heffeter P, Arion VB, Jakupec MA, Roller A, Galanski M, Berger W, Keppler BK. J. Med. Chem. 2009; 52 :5032. [ PubMed ] [ Google Scholar ]
9. Kowol CR, Berger R, Eichinger R, Roller A, Jakupec MA, Schmidt PP, Arion VB, Keppler BK. J. Med. Chem. 2007; 50 :1254. [ PubMed ] [ Google Scholar ]
10. Adsule S, Barve V, Chen D, Ahmed F, Dou QP, Padhye S, Sarkar FH. J. Med. Chem. 2006; 49 :7242. [ PubMed ] [ Google Scholar ]
11. Kovala-Demertzi D, Alexandratos A, Papageorgiou A, Yadav PN, Dalezis P, Demertzis MA. Polyhedron. 2008; 27 :2731. [ Google Scholar ]
12. Mendes IC, Soares MA, dos Santos RG, Pinheiro C, Beraldo H. Eur. J. Med. Chem. 2009; 44 :1870. [ PubMed ] [ Google Scholar ]
13. Kowol CR, Reisner E, Chiorescu I, Arion VB, Galanski M, Deubel DV, Keppler BK. Inorg. Chem. 2008; 47 :11032. [ PubMed ] [ Google Scholar ]
14. Enyedy EA, Nagy NV, Zsigo E, Kowol CR, Arion VB, Keppler BK, Kiss T. Eur. J. Inorg. Chem. 2010; 11 :1717. [ Google Scholar ]
15. Kowol CR, Trondl R, Arion VB, Jakupec MA, Lichtscheidl I, Keppler BK. Dalton Trans. 2010; 39 :704. [ PubMed ] [ Google Scholar ]
16. Leggett DJ, McBryde WAE. Talanta. 1974; 21 :1005. [ PubMed ] [ Google Scholar ]
17. Pessoa MMB, Andrade GFS, Monteiro VRP, Temperini MLA. Polyhedron. 2001; 20 :3133. [ Google Scholar ]
18. Izmailov NA. Electrochemistry of solutions. 2nd ed. Khimia; Moscow: 1966. [ Google Scholar ]
19. Borges RU, Paniago E, Beraldo H. J. Inorg. Biochem. 1997; 65 :267. [ PubMed ] [ Google Scholar ]
20. Motekaitis RJ, Martell AE. Inorg. Chim. Acta. 1991; 183 :71. [ Google Scholar ]
21. Santos MA, Gil M, Marques S, Gano L, Cantinho G, Chaves S. J. Inorg. Biochem. 2002; 92 :43. [ PubMed ] [ Google Scholar ]
22. Martell AE, Smith RM, Motekaitis RJ, editors. Critically Selected Stability Constants of Metal Complexes Database. College Station TX; 1997. Version 4.0. [ Google Scholar ]
23. García-Tojal J, Donnadieu B, Costes JP, Serra JL, Lezama L, Rojo T. Inorg. Chim. Acta. 2002; 333 :132. [ Google Scholar ]
24. Richardson DR, Kalinowski DS, Richardson V, Sharpe PC, Lovejoy DB, Islam M, Bernhardt PV. J. Med. Chem. 2009; 52 :1459. [ PubMed ] [ Google Scholar ]
25. Chan J, Thompson AL, Jones MW, Peach JM. Inorg. Chim. Acta. 2010; 363 :1140. [ Google Scholar ]
26. Gomez-Hens A, Valcarcel M. Microchem. J. 1984; 29 :253. [ Google Scholar ]
27. Gran G. Acta Chem. Scand. 1950; 4 :559. [ Google Scholar ]
28. Avdeef A, Box KJ, Comer JEA, Gilges M, Hadley M, Hibbert C, Patterson W, Tam KY. J. Pharm. Biomed. Anal. 1999; 20 :631. [ PubMed ] [ Google Scholar ]
29. Irving HM, Miles MG, Pettit LD. Anal. Chim. Acta. 1967; 38 :475. [ Google Scholar ]
30. SCQuery, The IUPAC Stability Constants Database. Royal Society of Chemistry; 1993-2005. Academic Software (Version 5.5) [ Google Scholar ]
31. Sabatini A, Vacca A, Gans P. Talanta. 1974; 21 :53. [ PubMed ] [ Google Scholar ]
32. Zékány L, Nagypál I. In: Computational Methods for the Determination of Stability Constants. Leggett DL, editor. Plenum Press; New York: 1985. p. 291. [ Google Scholar ]
33. Baes CF, Mesmer RE. The Hydrolysis of Cations. Wiley; New York: 1976. [ Google Scholar ]
34. Farkas E, Kozma E, Kiss T, Toth I, Kurzak B. J. Chem. Soc., Dalton Trans. 1995:477. [ Google Scholar ]
35. Sigel H, Zuberbühler AD, Yamauchi O. Anal. Chim. Acta. 1991; 255 :63. [ Google Scholar ]
36. Wirgau JI, Spasojevic I, Boukhalfa H, Baticic-Haberle I, Crumbliss AL. Inorg. Chem. 2002; 41 :1464. [ PubMed ] [ Google Scholar ]
1. West DX, Padhye SB, Sonawane PB. Struct. Bonding (Berlin) 1991; 76 :1. [ Google Scholar ] [ Ref list ]
2. Nutting CM, van Herpen CML, Miah AB, Bhide SA, Machiels JP, Buter J, Kelly C, de Raucourt D, Harrington KJ. Ann. Oncol. 2009; 20 :1275. [ PubMed ] [ Google Scholar ] [ Ref list ]
3. Richardson DR, Sharpe PC, Lovejoy DB, Senatatne D, Kalinowski DS, Islam M, Bernhardt PV. J. Med. Chem. 2006; 49 :6510. [ PubMed ] [ Google Scholar ] [ Ref list ]
4. Yu Y, Kalinowski DS, Kovacevic Z, Siafakas AR, Jansson PJ, Stefani C, Lovejoy DB, Sharpe PC, Bernhardt PV, Richardson DR. J. Med. Chem. 2009; 52 :5271. [ PubMed ] [ Google Scholar ] [ Ref list ]
5. Whitnall M, Howard J, Ponka P, Richardson DR. Proc. Natl. Acad. Sci. U. S. A. 2006; 103 :14901. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
6. Birch N, Wang X, Chong HS. Expert Opin. Ther. Pat. 2006; 16 :1533. [ Google Scholar ] [ Ref list ]
7. Shao J, Zhou B, Di Bilio AJ, Zhu L, Wang T, Shih CQJ, Yen Y. Mol. Cancer Ther. 2006; 5 :586. [ PubMed ] [ Google Scholar ] [ Ref list ]
9. Kowol CR, Berger R, Eichinger R, Roller A, Jakupec MA, Schmidt PP, Arion VB, Keppler BK. J. Med. Chem. 2007; 50 :1254. [ PubMed ] [ Google Scholar ] [ Ref list ]
10. Adsule S, Barve V, Chen D, Ahmed F, Dou QP, Padhye S, Sarkar FH. J. Med. Chem. 2006; 49 :7242. [ PubMed ] [ Google Scholar ] [ Ref list ]
13. Kowol CR, Reisner E, Chiorescu I, Arion VB, Galanski M, Deubel DV, Keppler BK. Inorg. Chem. 2008; 47 :11032. [ PubMed ] [ Google Scholar ] [ Ref list ]
8. Kowol CR, Trondl R, Heffeter P, Arion VB, Jakupec MA, Roller A, Galanski M, Berger W, Keppler BK. J. Med. Chem. 2009; 52 :5032. [ PubMed ] [ Google Scholar ] [ Ref list ]
14. Enyedy EA, Nagy NV, Zsigo E, Kowol CR, Arion VB, Keppler BK, Kiss T. Eur. J. Inorg. Chem. 2010; 11 :1717. [ Google Scholar ] [ Ref list ]
15. Kowol CR, Trondl R, Arion VB, Jakupec MA, Lichtscheidl I, Keppler BK. Dalton Trans. 2010; 39 :704. [ PubMed ] [ Google Scholar ] [ Ref list ]
16. Leggett DJ, McBryde WAE. Talanta. 1974; 21 :1005. [ PubMed ] [ Google Scholar ] [ Ref list ]
17. Pessoa MMB, Andrade GFS, Monteiro VRP, Temperini MLA. Polyhedron. 2001; 20 :3133. [ Google Scholar ] [ Ref list ]
18. Izmailov NA. Electrochemistry of solutions. 2nd ed. Khimia; Moscow: 1966. [ Google Scholar ] [ Ref list ]
20. Motekaitis RJ, Martell AE. Inorg. Chim. Acta. 1991; 183 :71. [ Google Scholar ] [ Ref list ]
22. Martell AE, Smith RM, Motekaitis RJ, editors. Critically Selected Stability Constants of Metal Complexes Database. College Station TX; 1997. Version 4.0. [ Google Scholar ] [ Ref list ]
19. Borges RU, Paniago E, Beraldo H. J. Inorg. Biochem. 1997; 65 :267. [ PubMed ] [ Google Scholar ] [ Ref list ]
21. Santos MA, Gil M, Marques S, Gano L, Cantinho G, Chaves S. J. Inorg. Biochem. 2002; 92 :43. [ PubMed ] [ Google Scholar ] [ Ref list ]
23. García-Tojal J, Donnadieu B, Costes JP, Serra JL, Lezama L, Rojo T. Inorg. Chim. Acta. 2002; 333 :132. [ Google Scholar ] [ Ref list ]
24. Richardson DR, Kalinowski DS, Richardson V, Sharpe PC, Lovejoy DB, Islam M, Bernhardt PV. J. Med. Chem. 2009; 52 :1459. [ PubMed ] [ Google Scholar ] [ Ref list ]
25. Chan J, Thompson AL, Jones MW, Peach JM. Inorg. Chim. Acta. 2010; 363 :1140. [ Google Scholar ] [ Ref list ]
26. Gomez-Hens A, Valcarcel M. Microchem. J. 1984; 29 :253. [ Google Scholar ] [ Ref list ]
27. Gran G. Acta Chem. Scand. 1950; 4 :559. [ Google Scholar ] [ Ref list ]
28. Avdeef A, Box KJ, Comer JEA, Gilges M, Hadley M, Hibbert C, Patterson W, Tam KY. J. Pharm. Biomed. Anal. 1999; 20 :631. [ PubMed ] [ Google Scholar ] [ Ref list ]
29. Irving HM, Miles MG, Pettit LD. Anal. Chim. Acta. 1967; 38 :475. [ Google Scholar ] [ Ref list ]
30. SCQuery, The IUPAC Stability Constants Database. Royal Society of Chemistry; 1993-2005. Academic Software (Version 5.5) [ Google Scholar ] [ Ref list ]
31. Sabatini A, Vacca A, Gans P. Talanta. 1974; 21 :53. [ PubMed ] [ Google Scholar ] [ Ref list ]
32. Zékány L, Nagypál I. In: Computational Methods for the Determination of Stability Constants. Leggett DL, editor. Plenum Press; New York: 1985. p. 291. [ Google Scholar ] [ Ref list ]
33. Baes CF, Mesmer RE. The Hydrolysis of Cations. Wiley; New York: 1976. [ Google Scholar ] [ Ref list ]
34. Farkas E, Kozma E, Kiss T, Toth I, Kurzak B. J. Chem. Soc., Dalton Trans. 1995:477. [ Google Scholar ] [ Ref list ]
35. Sigel H, Zuberbühler AD, Yamauchi O. Anal. Chim. Acta. 1991; 255 :63. [ Google Scholar ] [ Ref list ]
36. Wirgau JI, Spasojevic I, Boukhalfa H, Baticic-Haberle I, Crumbliss AL. Inorg. Chem. 2002; 41 :1464. [ PubMed ] [ Google Scholar ] [ Ref list ]

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a Department of Inorganic and Analytical Chemistry, University of Szeged, P.O. Box 440, H-6701, Szeged, Hungary. mehc@ydeyne . u-szeged.hu; Fax: +36 62 420505

b University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090, Vienna, Austria

b University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090, Vienna, Austria

b University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090, Vienna, Austria

a Department of Inorganic and Analytical Chemistry, University of Szeged, P.O. Box 440, H-6701, Szeged, Hungary. mehc@ydeyne . u-szeged.hu; Fax: +36 62 420505

c Bioinorganic Chemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, P.O. Box 440, Szeged, H-6701, Hungary

b University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090, Vienna, Austria

Stoichiometry and stability of Ga III , Fe III , Fe II complexes of Triapine and five related α- N heterocyclic thiosemicarbazones with potential antitumor activity have been determined by pH-potentiometry, UV-vis spectrophotometry, 1 H NMR spectroscopy, and spectrofluorimetry in aqueous solution (with 30% DMSO), together with the characterization of the proton dissociation processes. Additionally, the redox properties of the iron complexes were studied by cyclic voltammetry at various pH values. Formation of high stability bis -ligand complexes was found in all cases, which are predominant at physiological pH with Fe III /Fe II , whilst only at the acidic pH range with Ga III . The results show that among the thiosemicarbazones with various substituents the N-terminal dimethylation does not exert a measurable effect on the redox potential, but has the highest impact on the stability of the complexes as well as the cytotoxicity, especially in the absence of a pyridine-NH 2 group in the molecule. In addition the fluorescence properties of the ligands in aqueous solution and their changes caused by Ga III were studied.
Thiosemicarbazones (TSCs) are extensively investigated as they exhibit anticancer, antibacterial, antiviral and other biological properties. 1 Especially α- N -heterocyclic TSCs with a nitrogen containing heterocycle in α position to the thiosemicarbazide side chain exert significant antitumor activity in vitro and in vivo . The proposed mechanism of action is based on their ability to inhibit the iron-requiring enzyme ribonucleotide reductase (RR), the rate determining enzyme in the supply of deoxyribonucleotides for DNA synthesis required for cell proliferation. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP, see Scheme 1 ) is the most prominent representative among these compounds as it has been tested in a variety of tumor cell lines in the preclinical setting and is currently undergoing different phase I and II clinical trials. 2 Also di-2-pyridyl TSCs were found to be highly potent against melanoma, breast cancer and neuroepithelioma cells 3 , 4 and their anticancer activity was confirmed in vivo in several human xenografts in mice. 5
Ligands used in this study: Triapine = 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; FTSC = 2- f ormylpyridine t hio s emi c arbazone; PTSC = p yridine-2-carboxaldehyde N 4 , N 4 -dimethyl- t hio s emi c arbazone; APTSC = 3- a mino p yridine-2-carboxaldehyde N 4 , N 4 -dimethyl t hio s emi c arbazone; FaTSC = 2-pyridine f orm a mide t hio s emi c arbazone; AcTSC = 2- ac etylpyridine t hio s emi c arbazone.
Compounds bearing the α-pyridyl TSC backbone are known to possess strong iron chelating properties. 6 It was suggested that the formation of an intracellular iron complex plays a crucial role in the mechanism of enzyme inhibition. The iron-TSC complexes have to be redox active to undergo redox-cycling and generate reactive oxygen species (ROS), which are able to quench the active site tyrosyl radical of the RR required for the enzymatic activity. 7 This mechanism is suggested to be at least partially responsible for the antiproliferative activity of TSCs. As a result, the coordination chemistry of Fe II and Fe III complexes of TSCs has been receiving considerable attention, nowadays. Coordination of TSCs to iron occurs usually via tridentate (N(pyr),N 1 ,S − ) binding. 6 - 9 This arrangement of the donor atoms is also suitable for coordination to other transition metal ions, e.g. Cu II , Zn II , Ru III , Pd II and Ga III , which can result in complexes with higher cytotoxicity than that of the metal-free ligand alone. 10 - 13
In our previous work a series of Fe III and Ga III complexes of some derivatives of Triapine was synthesized and studied for their antitumor potency together with that of the metal-free ligands. 8 These investigations showed that the dimethylation of the terminal nitrogen (N 4 ) strongly enhances the cytotoxicity of the TSCs and that of their Fe III and Ga III complexes. However, this increase can only be observed in the absence of any NH 2 group in the molecule. The characterization of the complexes was performed in solid phase or in solution of organic solvents. However, the knowledge of the speciation and the most plausible chemical forms of these complexes in aqueous solution at physiological pH is a mandatory prerequisite for understanding the alterations in the efficacy of the complexes formed with Triapine and its derivatives and may be useful for the design of more effective chemotherapeutics. Quite little information is available in the literature about the thermodynamic stability of these complexes. In particular, although it is thought that the iron complex of Triapine is the active species inside the cells the stability constants of Fe III have not been reported so far and no data for Ga III -TSC complexes are available.
Therefore, detailed pH-potentiometric, UV-vis spectrophotometric, 1 H NMR spectroscopic and spectrofluorimetric measurements have been performed to investigate the stoichiometry and stability of F
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