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 beta-D-glucuronidase. The inhibitory effects of T1 and T2 were comparable to Vorinostat in the presence of beta-D-glucuronidase, but were higher than 10 mu M in the absence of beta-D-glucuronidase. Therefore, T1 and T2 are promising candidates for in vivo investigations with high potential to be the target water-soluble prodrugs. IC50 values of Belinostat derivatives T3 and T4 were not affected by beta-D-glucuronidase, but T3 and T4 had the excellent cell proliferation inhibition on Hut-78.