ИСТИНА

Isoflavones, which are a subclass of isoflavonoids, are compounds that belong to plant secondary metabolites and demonstrate a broad spectrum of biological activities(1). 7,8-Dihydro-4H-chromene-4,5(6H)-diones can be considered as saturated analogues of isoflavones, and there is only limited information about their methods of synthesis and application. 2-Acylcyclohexane-1,3-diones, having β-tricarbonyl polyfunctional group, can be used for preparation different classes of compounds(2). In this work, we report a facile and versatile method for the synthesis of 7,8-dihydro-4H-chromene-4,5(6H)-diones 4 from 2-(2-aryl)cyclohexane-1,3-diones 3 under the action of an N,N-dimethylformamide dimethyl sulfate adduct in the presence of triethylamine. A total of fifteen target compounds were synthesized using the developed scheme. In particular, we designed and synthesized compound tkt-4 as a potential HER2 inhibitor. Prepared compounds were tested against two HER2-positive cancer cell lines, BT474 (breast) and A431 (skin). Compounds rub-611 and tkt-4 effectively suppressed proliferation of cells of both lines. Compound rub-611 has IC50 value of 6.7 μM against BT474 cells and 5.5 μM against A431 cells. Compound tkt-4 has IC50 value of 13.3 μM against BT474 cells and 9.9 μM against A431 cells. Further, when compared to known anti-HER2 chemotherapeutic agents, both lead compounds were inferior in activity to lapatinib but were significantly more active than AG-825. In tests for inhibition of HER2, EGFR, and HER4 kinases, it was found that rub-611 at a dose of 1 μM effectively inhibits HER2 and HER4 (about 70% inhibition), while tkt-4 at the same dose is a selective inhibitor of HER2 (84% inhibition).