Design, synthesis, and biological evaluation of target water-soluble hydroxamic acid-based HDACi derivatives as prodrugs.

Four compounds T1, T2, T3, and T4 were designed and synthesized as Vorinostat and Belinostat derivatives being the target water-soluble prodrugs. The water solubility of Vorinostat derivatives, T1 and T2, exhibited 400- to 600-fold higher than that of Vorinostat, and Belinostat derivatives, T3 and T4, showed 600- to 750-fold higher than that of Belinostat. Four compounds were evaluated for their inhibitory activities against tumor cell lines HT-29 and Hut-78 in the absence or presence of β-D-glucuronidase.