1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part III.
New 5-(2-arylethenyl)-1, 2, 4-triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The desired products were obtained when the 5-methyl heterocycle reacted with the corresponding iminium electrophiles. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than Tirapazamine, 3-aminobenzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 11, 6-methyl-5-[2-(5-nitrofuryl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective. Some derivatives were studied as DNA-binding agents in oxic conditions showing poor affinity for this biomolecule. This result showed that the cytotoxic activity in oxia is DNA damage not dependent. Electrochemical and ESR spectroscopy studies were performed in order to determine the ability of compounds to produce radicals and the relation of these in the mechanism of cytotoxicity.
Cerecetto
Hugo
H
Departamento de Química Orgánica, Facultad de Química - Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
González
Mercedes
M
Risso
Mariela
M
Saenz
Patricia
P
Olea-Azar
Claudio
C
Bruno
Ana M
AM
Azqueta
Amaia
A
De Ceráin
Adela López
AL
Monge
Antonio
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D004563:Electrochemistry; D004578:Electron Spin Resonance Spectroscopy; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D014227:Triazines; C093444:1,2,4-triazine; D004247:DNA