1, 2, 4-Triazine N-oxide derivatives: studies as potential hypoxic cytotoxins. Part II.
New 1, 2, 4-Triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The starting heterocycles have been prepared using a standard microwave oven in a clean and good-yielded process. The reactivity of methyl-1, 2, 4-triazine N(4)-oxide and N(1), N(4)-dioxide with different electrophilic agents has been studied. The desired products were obtained only when iminium electrophiles were employed. The regioselectivity of this process has been studied by means of experimental and theoretical (at ab initio level) procedures. Theoretically was expected that the most stable intermediates where the benzylic-like anion from position 5. A fact which agreed with the experimental observed regioselectivity. 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-amino-benzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 19, 6-methyl-5-[2-(5-nitrothienyl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective.
Cerecetto
Hugo
H
Departamento de Química Orgánica, Facultad de Química - Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
González
Mercedes
M
Onetto
Silvia
S
Saenz
Patricia
P
Ezpeleta
Olga
O
De Ceráin
Adela López
AL
Monge
Antonio
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D014227:Triazines; C093444:1,2,4-triazine