Design, Synthesis and Mechanistic Study of New Dual Targeting HDAC/Tubulin Inhibitors

Abstract

<b>Aim:</b> The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin. <b>Materials & methods:</b> The target compounds (<b>3a-c, 4a-c</b> and <b>5a-c</b>) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs). <b>Results:</b> Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound <b>4b</b> possessed the highest potency; however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and six pockets and tubulin polymerization protein. <b>Conclusion:</b> Compound <b>4b</b> could be considered a good antitumor candidate to go further into <i>in vivo</i> and clinical studies.