2,3-Bis(2-pyridyl)-5,8-quinoxalinediones with metal chelating properties: Synthesis and biological evaluation
Sylviane Giorgi-Renault
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Search for more papers by this authorPatricia Gebel-Servolles
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Search for more papers by this authorPhilippe Helissey
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Search for more papers by this authorCorresponding Author
Jean Renault
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, FranceSearch for more papers by this authorJean-Luc Bernier
Unité 16 INSERM, Place de Verdun, 59045 Lille, France
Search for more papers by this authorJean-Pierre Henichart
Unité 16 INSERM, Place de Verdun, 59045 Lille, France
Search for more papers by this authorSuzanne Cros
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, CNRS, Toulouse, France
Search for more papers by this authorSylviane Giorgi-Renault
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Search for more papers by this authorPatricia Gebel-Servolles
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Search for more papers by this authorPhilippe Helissey
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Search for more papers by this authorCorresponding Author
Jean Renault
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France
Laboratoire de Recherche sur les heétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, FranceSearch for more papers by this authorJean-Luc Bernier
Unité 16 INSERM, Place de Verdun, 59045 Lille, France
Search for more papers by this authorJean-Pierre Henichart
Unité 16 INSERM, Place de Verdun, 59045 Lille, France
Search for more papers by this authorSuzanne Cros
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, CNRS, Toulouse, France
Search for more papers by this authorAbstract
The synthesis of 2,3-bis(2-pyridyl)-5,8-quinoxalinediones has been carried out in order to provide new antitumor drugs related to streptonigrin. Some derivatives have been found to possess significant cytotoxic properties and their mechanism of action has been studied. They were found to induce single-strand cleavage of covalently closed circular DNA (ccc-DNA). This biological activity requires an apparent in situ reduction (NADH activation) of the quinone to a hydroquinone or semiquinone radical, is facilitated by the presence of Cu(II), and involves activation of molecular oxygen to highly reactive radical species. Thus, although less active than the parent drugs, these molecules provide an attractive rationale for the observed cytotoxic and antitumor potency, as well as the cell-free single strand DNA cleavage efficacy of that family of drugs.
References and Notes
- 1 Marshall, L. E.; Graham, D. R.; Reich, K. A., Sigman, D. S. Biochemistry 1981, 20, 244–250.
- 2 Hertzberg, R. P.; Dervan, P. B. J. Am. Chem. Soc. 1982, 104, 313–315.
- 3 Dreyer, G. B.; Dervan, P. B. Proc. Natl. Acad. Sci. USA 1985, 82, 968–972.
- 4 Dervan, P. B.; Baker, B. F. Ann. N.Y. Acad. Sci. 1985, 471, 51–59.
- 5 Saryan, L. A.; Mailer, K.; Krishnamurti, C.; Antholine, W. E.; Petering, D. H. Biochem. Pharmacol. 1981, 30, 1595–1604.
- 6 Giloni, L.; Takeshita, M.; Johnson, F.; Iden, C.; Grollman, A. P. J. Biol. Chem. 1981, 256, 8608–8615.
- 7 Ueda, K.; Morita, J.; Yamashita, K.; Komano, T. Chem. Biol. Interact. 1980, 29, 145–158.
- 8 Iyengar, B. S.; Takahashi, T.; Remers, W. A.; Bradner, W. T. J. Med. Chem. 1986, 29, 144–147.
- 9 Rao, K. V. J. Pharm. Sci. 1979, 68, 853–856.
- 10 Sinha, B. K. Chem. Biol. Interact. 1981, 36, 179–188.
- 11 Hajdu, J.; Armstrong, E. C.. J. Am. Chem. Soc. 1981, 103, 232–234.
- 12 Cone, R.; Hasan, S. K.; Lown, J. W., Morgan, A. R. Can. J. Biochem. 1976, 54, 219–223.
- 13 Shaikh, I. A. Synthesis of streptonigrin analogues. Structure activity relationship and mechanism. State University of New York: Stony Brook, NY, 1983, pp 122–138; Chem. Abstr. 1984, 100, 103019a.
- 14 Lown, J. W.; Sim, S. K.; Chen, H. H. Can. J. Biochem. 1978, 56, 1042–1047.
- 15 Colton, D. F.; Geary, W. J. J. Chem. Soc. (A) 1971, 2457–2460.
- 16 McCoubrey, A.; Webster, W. J. Chem. Soc. 1948, 1719–1720.
- 17 Krammer, F. A.; West, R. J. Phys. Chem. 1965, 69, 673–674.
- 18 Zimmer, H.; Lankin, D. C.; Horgan, S. W. Chem. Rev. 1971, 71, 229–246.
- 19 Hendrickson, J. B.; de Vries, J. C. J. Org. Chem. 1982, 47, 1150–1152.
- 20 Tsizin, Y. S. Chem. Heterocycl. Comp. 1978, 925–940.
- 21
Kende, A. S.;
Naegly, P. C.
Tetrahedron Lett.
1978,
48, 4775–4778.
10.1016/S0040-4039(01)85728-2 Google Scholar
- 22 Lin, A. J.; Lillis, B. J.; Sartorelli, A. C. J. Med. Chem. 1975, 18, 917–912.
- 23 Lown, J. W.; Sim, S. K. Can. J. Biochem. 1976, 54, 446–452.
- 24 Renault, J.; Baron, M.; Mailliet, P.; Giorgi-Renault, S.; Paoletti, C.; Cros, S. Eur. J. Med. Chem. 1981, 16, 545–550.
- 25 Lin, A. J.; Antonelli, I.; Cosby, L. A.; Sartorelli, A. C. J. Med. Chem. 1984, 27, 813–815 and references cited therein.
- 26 Moore, H. W. Science 1977, 197, 527–532.
- 27 Giorgi-Renault, S.; Renault, J.; Baron, M.; Servolles, P.; Paoletti, C.; Cros, S. Eur. J. Med. Chem. 1985, 20, 144–148.
- 28 Antonini, I.; Lin, T. S.; Cosby, L. A.; Dai, Y. R.; Sartorelli, A. C. J. Med. Chem. 1982, 25, 730–735.
- 29 Paull, K. D.; Zee-Cheng, R. K. Y.; Cheng, C. C. J. Med. Chem. 1976, 19, 337–339.
- 30 Lin, T. S.; Teicher, B. A.; Sartorelli A. C. J. Med. Chem. 1980, 23, 1237–1242.
- 31 Ping Yuan Yeh J. Chinese Chem. Soc. (Taiwan) 1954, 1, 106–112; Chem. Abstr. 1956, 50, 262f.
- 32 Merchant, J. R.; Rege, D. V. Tetrahedron 1971, 27, 4837–4842.
- 33 Driscoll, J. S.; Dudeck, L.; Gongleton, G.; Veran, R. I. J. Pharm. Sci. 1979, 68, 185–188.
- 34 Renault, J.; Giorgi-Renault, S.; Baron, M.; Mailliet, P.; Paoletti, C.; Cros, S.; Voisin, E. J. Med. Chem. 1983, 26, 1715–1719.
- 35 Cohen, G.; Eisenberg, H. Biopolymers 1966, 4, 429–439.
- 36 Cohen, G.; Eisenberg, H. Biopolymers 1969, 8, 45–55.
- 37 Reinert, K. E. J. Mol. Biol. 1972, 72, 593–607.
- 38 Peisach, J.; Blumberg, N. E. Arch. Biochem. Biophys. 1974, 165, 691–708.
- 39 Cassis, R.; Walderrama, J. A. Synth. Commun. 1983, 13, 347–356.
- 40 Renault, J.; Giorgi-Renault, S.; Mailliet, P.; Baron, M.; Paoletti, C.; Cros, S. Eur. J. Med. Chem. 1981, 16, 24–34.
- 41 Wakelin, L. P. G.; Waring, M. J. Biochem. J. 1976, 157, 721–739.
