1, 2, 4‐Triazine N‐oxide Derivatives: Studies as Potential Hypoxic Cytotoxins. Part II.

Abstract

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.

New hits as phase II enzymes inducers from a focused library with heteroatom–heteroatom and Michael-acceptor motives

“…Consequently, we selected new derivatives of the 1,2,4-triazine 4-oxide system modifying substituents at the 3- and 5-position of the heterocycle and the level of oxidation (derivatives [29–36], Table 3) [25,34,35]. With these results we could identify new 1,2,4-triazine 4-oxides with better activities than the parent compounds, (10) , (23) and (25) , being derivatives (31) and (32) the best monofunctional inductors of phase II enzymes in both cellular systems in the assayed conditions (r H /B = 1.01 and r H /B = 1.03, respectively).…”

Influence of N-Oxide Introduction on the Stability of Nitrogen-Rich Heteroaromatic Rings: A Quantum Chemical Study

“…The molecular structures of all the objectives with bond length in Å are shown in Schemes –. Some of these molecules or their analogues have already been reported previously, such as A1–1, A2–1, B2–1, C1–2, E1–1, F1–1, G1, G1–1, G1–2, G2–1, H1, H1–1, H1–2, H2, H2–1, H2–5, H3, I1, I1–1, I1–4, and J1, providing sufficient bases for comparing the calculated and experimental results.…”

Six‐Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

“…Significant activity towards leukemia, ovarian cancer and anti-HIV were observed in vitro for some 3,5,6-trisubstituted-1,2,4-triazines [203][204][205][206][207][208]. 1,2,4-Triazine-N-oxide derivatives have been studied as potential hypoxic cytoxins [209][210][211]. Recently, the pyrrolotriazine nucleus has been identified as a potent and selective inhibitor of the tyrosine kinase [212][213][214].…”