Uses of cyclohexan‐1,3‐dione for the synthesis of tetrahydrochromeno[3,4‐c]chromen derivatives with anti‐tumor activities

Abstract

AbstractCyclohexan‐1,3‐dione (1) was used as the key starting material, which reacted with salicylaldehyde (2) and either malononitrile (3a) or ethyl cyanoacetate (3b) in ethanol containing a catalytic amount of triethylamine to give the 3,4,7,12b‐tetrahydrochromeno[3,4‐c]chromen‐1‐one derivatives 5a,b. The latter compounds underwent Gewald's thiophene synthesis through the reaction with either malononitrile or ethyl cyanoacetate to give compounds 6a‐d, respectively. On the other hand, compound 5a was used for the synthesis of annulated chromeno[3,4‐c]chromen derivatives through its reaction with different chemical reagents. The synthesized compounds were evaluated against the six cancer cell lines A549, HT‐29, MKN‐45, U87MG, SMMC‐7721, and H460 using the standard MTT assay in vitro, with foretinib as the positive control, many compounds expressed high inhibitions. The most active compounds 5b, 6b, 6d, 7, 9b, 11a, 11b, 13, 17, 18b, 20b, 21b, 21e, and 21f were selected for inhibition of five tyrosine kinases and some selected compounds for Pim‐1 kinase inhibition. The results showed that compounds 6b, 6d, 11a, 13, 17, 20b, and 21e were the most potent compounds with the tyrosine kinases and compounds 6d, 11a, 20b, and 21e were the most potent inhibitors of Pim‐1 kinase.