title: Novel Cu(II) quinoxaline N1,N4-dioxide complexes as selective hypoxic cytotoxins.
abstract: As an effort to develop novel selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of quinoxaline N1,N4-dioxide derivatives (L1 = 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N1,N4-dioxide, L2 = 3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide and L3 = 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide) and to get a synergism among metals and these type of bioreductive agents, L2 and three novel Cu(II) complexes of general formulae [Cu(II)(H2O)x(L - H)2], where L = L1 (x = 1), L2 (x = 0) or L3 (x = 2) were developed. L2 and complexes were synthesized and structurally characterized by elemental and thermal analyses, and FTIR, electronic, MS, NMR, and EPR spectroscopies. The new compounds were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes showed excellent selective cytotoxicity in hypoxia, being their cytotoxicity similar to or higher than that of the ligands L1-L3. Besides, the copper complexes were so poorly cytotoxic in oxia as the free ligands. In addition, for the first time Cu(II)-quinoxaline complexes are reported as a family of hypoxic cytotoxins.
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11200 Montevideo, Uruguay. mtorre@fq.edu.uy
authors.forename: María H
authors.initials: MH
authors.lastname: Torre
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
authors.forename: Jeannette
authors.initials: J
authors.lastname: Araujo
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: María Laura
authors.initials: ML
authors.lastname: Lavaggi
authors.forename: Amaya
authors.initials: A
authors.lastname: Azqueta
authors.forename: Adela
authors.initials: A
authors.lastname: López de Cerain
authors.forename: Antonio Monge
authors.initials: AM
authors.lastname: Vega
authors.forename: Ulrich
authors.initials: U
authors.lastname: Abram
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Costa-Filho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D005347:Fibroblasts; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013055:Spectrophotometry, Infrared; D013499:Surface Properties
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011810:Quinoxalines; D003300:Copper; C003282:quindoxin