2,3-bis(2-pyridyl)-5,8-quinoxalinediones with metal chelating properties: synthesis and biological evaluation.
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.
Giorgi-Renault
S
S
Laboratoire de Recherche sur les hétérocycles azotés, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, Paris, France.
Gebel-Servolles
P
P
Helissey
P
P
Renault
J
J
Bernier
J L
JL
Henichart
J P
JP
Cros
S
S
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D003300:Copper; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D005453:Fluorescence; D005609:Free Radicals; D007939:Leukemia L1210 / Q000473:pathology; D009691:Nucleic Acid Denaturation; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D014783:Viscosity
D002614:Chelating Agents; D005609:Free Radicals; D011725:Pyridines; D011810:Quinoxalines; D003300:Copper; D004247:DNA