Anti-tumor potential of substituted 6-oxo(thioxo)-6,7-dihydro-2H-[1,2,4]triazino[2,3-с]quinazolin-2-ones

Abstract

Quinazoline moiety may be found in structure of drugs that reveal wide spectrum of biological activity1, including anti-tumor effect2. Some of the quinazoline derivatives, namely 4-R-phenylaminoquinazolines («Gefitinib», «Erlotinib», «Vandetanib», «Lapatinib» etc) are inhibitors of CDK2 and p38 kinases, epidermal growth factor receptor, vascular endothelial growth factor and currently used in clinical oncology3. It should be mentioned, that antitumor activity of 4-R-phenylaminoquinazolines caused is determined by as nature of basic heterocyclic fragment, so by structure of aniline fragment in position 4. The presence of halogen, hydroxy-group or cyano-group in aniline moiety is essential for the presence of anticancer activity as well. The introduction of additional functional groups to position 6 and 7 is also reasonable for improvement of pharmacokinetic properties, namely bioavailability and lipophilicity. Thus, introduction of vinyl, but-2-ynamide fragments to the molecule increase the metabolic and excretion rate and consequently decrease cumulation of compounds. At the same time presence of alkoxy-groups and saturated nitrogen-containing moities and oxygen containing heterocyclic fragments is essential for hydrophobic interaction with target enzyme4. Moreover, recently, it was shown that annulation of heterocyclic fragment to pyrimidine ring (bioisosteric substitution) resulted the extension of anti-cancer activity spectrum, increasing of anti-cancer activity and decreasing of the agent’s toxicity5.