Anticancer activity of some newly synthesized pyrano[2,3-d][1,2,3]triazine derivatives using 1-(7-hydroxy-2,2-dimethylchroman-6-yl)ethanone as synthon

A series of the newly substituted pyrano[1,2,3]triazine derivatives 3–14 were synthesized using compounds 1 and 2 as starting materials. Compound 2 was methylated using methyl iodide to compound 3, which was treated with aromatic aldehydes to give acryloyl derivatives 4a–c. Compounds 4a,b were reacted with ethyl cyano-acetate to give pyran-3-carboxylates 5a,b which were reacted with ethyl glycinate hydrochloride to give 6a,b. Treatment of 6a,b with hydrazine hydrate gives acid hydrazides 7a,b, which were reacted with 5,5-dimethyl-1,3-cyclohexanedione to give acetohydrazides 8a,b. Cyclization of 8b with 2-(4-nitrobenzylidene)malononitrile afforded hexahydroquinoline 9. However, the acridindione 10 was synthesized by heating of 8b with 2-(4-nitrobenzylidene)malononitrile in acetic acid containing few drops of triethylamine. Treatment of 7a,b with phenyl isothiocyanate or 2,5-hexanedione or phthalic anhydride gave compounds 11a,b, 13a,b and 14a,b, respectively. In the present work, all the selected pyrano[1,2,3]trizine derivatives were soluble in DMSO at concentrations high enough to allow cell experiments, and the in vitro biological activity of these compounds was evaluated by their growth inhibitory potency in liver HEPG2 cancer cell lines. The cytotoxic potency of compounds 3–14 was studied in comparison to the known anticancer drugs 5-fluorouracil and doxorubicin.