New, Substituted Derivatives of Dicarboximides and their Cytotoxic Properties

Abstract

A large group of aminoalkyl and aminoalkanol derivatives of selected dicarboximides were synthesized and characterized by 1HNMR, 13CNMR and ESI MS spectra analysis. The thirty nine new compounds were tested for their cytotoxic properties in human chronic (K562), acute leukemia (HL-60), and cervical cancer cells (HeLa) as well as in normal endothelial cells (HUVEC). The most promising compounds are 4-[2-(dimethylamino)ethyl]-, (diethylamino) ethyl]-, 4-[2-(piperidin-1-yl)ethyl]-, 4-[3-(dimethylamino)propyl]- and 4-[2-hydroxy-3-(propan- 2-ylamino)propyl]- derivatives of 1,7-diethyl-8,9-diphenyl-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5,10-trione exhibiting high and selective cytotoxicity towards K562 and HL-60 cells (IC50 in the range of 1-10 µM) while being non-toxic towards HUVEC and HeLa cells (IC50> 100 μM). Moreover, the preliminary studies have showed that 4-[2-(piperidin-1-yl)ethyl]- 1,7-diethyl-8,9-diphenyl-4-azatricyclo [5.2.1.0(2,6)]dec-8-ene-3,5,10-trione induces programmed cell death (apoptosis) in leukemia cells.

New Thalidomide-Resembling Dicarboximides Target ABC50 Protein and Show Antileukemic and Immunomodulatory Activities

“…We have earlier shown [20] that dicarboximides 15 were highly cytotoxic towards human leukemia cells K562 and HL-60. Interestingly, these compounds were neither cytotoxic to adherent cancer cells (HeLa) nor to primary endothelial cells (HUVEC).…”

“…Dicarboximides 1 – 6 (Table 1) were synthesized according to previously reported procedures [20,21]. Compounds 6a , 6b , 7 – 9 were synthesized as described below.…”

“…The starting imide D was prepared by the methods described earlier [20]. A mixture of 1,2,3,4-tetraphenylcyclopenta-1,3-diene (0.02 mol) and maleimide (0.022 mol) was heated for 6 h in 20 mL of benzene.…”

“…The amino alkanol derivative 6a was obtained in two-step reaction (Scheme 1) according to the method described previously [20].…”

“…In the present study we investigated pro-apoptotic properties and the mechanism of cytotoxicity of new derivatives of dicarboximides. These compounds were earlier found to be remarkably cytotoxic and selective towards human leukemia cells (K562, HL-60), and non-toxic to adherent cancer cells (HeLa, human cervix carcinoma) and to primary endothelial cells (HUVEC, human umbilical vein endothelial cells) [19,20]. We identified cellular proteins targeted by these compounds and investigated their immunomodulatory activity.…”