The College of Pharmacy discussed the master’s thesis entitled Design, Synthesis, and Preliminary Antiproliferative Evaluation of New Histone Deacetylase Inhibitors with Isoxazole Moiety as Zinc-Binding Group by the student Ali Mohammed Saeed Abulameer and his supervisor, Assistant Professor Dr. Ayad Abed Ali Al-Hamashi, in the Pharmaceutical Chemistry Department.
Based on the molecular modeling studies, the newly designed isoxazole-based histone deacetylase (HDAC) inhibitors were docked against different isoforms using the Schrodinger modeling suite. Compounds with isoxazole moiety were linked to the cap and linker to give the final compounds that showed virtual bidentate zinc chelation in the HDACs active site, which is important for the inhibition. The organic synthesis of the final compounds began with the protection of 4-aminobenzylalcohol using silyl chloride, followed by amide bond formation with carboxylic acid under mild conditions. Deprotection of silyl was performed under mild conditions using simple stirring with acetyl chloride to give key intermediates, which were then linked to isoxazole by an ether bond or ester bond to afford the final products. The reactions were monitored using thin-layer chromatography to ensure the completion of the reactions and predict the best method for purification using column chromatography.
The final compounds were characterized using infrared spectroscopy and nuclear magnetic resonance spectroscopy. An evaluation of preliminary antiproliferative activities against colon cancer cell lines showed that the compound linked to isoxazole by ether linkage has an antiproliferative activity of low micromolar IC50, which is comparable to the FDA-approved HDAC inhibitor vorinostat.
