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.

Abstract 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.