A facile method for the preparation of 7,8-dihydro-4H-chromene-4,5(6H)-diones as non-aromatic cycle A analogs of isoflavones and their evaluation as antiproliferative agents

In this article, we describe a facile method for the synthesis of a novel class of compounds - 3-aryl-7,8-dihydro-4H-chromene-4,5(6H)-diones. The target compounds were prepared from easily accessible 2-(2-arylacetyl)cyclohexane-1,3-diones using a low-cost dimethylformamide-dimethyl sulfate adduct in the presence of triethylamine. The obtained compounds, which can be considered non-aromatic cycle A analogs of Isoflavones, demonstrated moderate antiproliferative activity in the micromolar IC₅₀ range and modest selectivity toward HER2-positive Cancer cells. A molecular modeling study suggested that their possible mechanism of action may involve HER2 inhibition. Additionally, by introducing a 3-chloro-4-((3-fluorobenzyl)oxy)phenyl group into the structure of the reported compounds, we designed and synthesized compound 4o as a potential selective HER2 inhibitor. Two compounds, 4b and 4o, which had different predicted binding modes to HER2, were tested in vitro for kinase activity inhibition against eight tyrosine kinases. At a concentration of 1 μM, compound 4b inhibited HER2 and HER4 by 74 % and 69 %, respectively. At the same concentration, compound 4o significantly inhibited only HER2 by 84 %. However, immunoblotting in A431 cells treated with 4b or 4o unexpectedly showed a reduction in total HER2 expression rather than in phosphorylated HER2 (p-HER2). Furthermore, both compounds reduced cyclin D1 level and stimulated PARP cleavage.

7,8-dihydro-4H-chromene-4,5(6H)-diones; Antiproliferative activity; HER2; Isoflavones; Isoflavonoids.