Cell differentiation enhancement by hydrophilic derivatives of 4,8-Dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-diones in HL-60 leukemia cells

Among five carboxamide derivatives (13–17), N-(2-dimethylaminoethyl)-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione-2-carboxamide (13) showed the greatest enhancement of all-trans retinoid acid (ATRA)-induced differentiation in HL-60 cells, inducing nearly complete differentiation at a concentration of 0.02 μM. On the other hand, 2-hydroxymethyl-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (2) and 2-(1-hydroxylethyl)-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (18) exhibited excellent and equally potent differentiation effects on HL-60 cells. To improve their water solubility, ester-type hydrophilic prodrugs (23–26) were also synthesized. Compounds 13 and 23–26 are identified in this paper as new anti-leukemic drug candidates.

Graphical abstractN-(2-dimethylaminoethyl)-4,8-dihydrobenzo[1,2-b:5,4-b′]-dithiophene-4,8- dione-2-carboxamide (13) and 2-(1-hydroxyethyl)-4,8-dihydrobenzo[1,2-b:5,4-b′]dithiophene-4,8-dione (18) were found to exhibit excellent differentiation effects on HL-60 cells. To improve the water solubility of compound 18, its ester-type hydrophilic prodrugs (23-26) was synthesized.Figure optionsDownload full-size imageDownload as PowerPoint slide