Novel Cu(II) quinoxaline N1,N4-dioxide complexes as selective hypoxic cytotoxins.
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.
Torre
María H
MH
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11200 Montevideo, Uruguay. mtorre@fq.edu.uy
Gambino
Dinorah
D
Araujo
Jeannette
J
Cerecetto
Hugo
H
González
Mercedes
M
Lavaggi
María Laura
ML
Azqueta
Amaya
A
López de Cerain
Adela
A
Vega
Antonio Monge
AM
Abram
Ulrich
U
Costa-Filho
Antonio J
AJ
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
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011810:Quinoxalines; D003300:Copper; C003282:quindoxin