Design, Synthesis and Mechanistic Study of New Dual Targeting HDAC/Tubulin Inhibitors
Mona S. El‐Zoghbi, Amr K. A. Bass, Gamal El‐Din A. Abuo‐Rahma, Mamdouh F. A. Mohamed, Mohamed Badr, Hanan Al-Ghulikah, Elshimaa M. N. Abdelhafez
Abstract
Aim: 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. Materials & methods: The target compounds (3a–c, 4a–c and 5a–c) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs). Results: Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound 4b 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. Conclusion: Compound 4b could be considered a good antitumor candidate to go further into in vivo and clinical studies.