Design and Synthesis of Novel Uracil-Linked Schiff Bases As Dual Histone Deacetylase Type II/topoisomerase Type I Inhibitors With Apoptotic Potential

Abstract

Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (19–30) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC50 values against HDAC II and Topo I of 1.12 and 13.44 μM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.

Evaluation of 1,10-phenanthroline-based hydroxamate derivative as dual histone deacetylases/ribonucleotide reductase inhibitor with antitumor activities

“…The incorporation of unique structural motifs enhances selectivity and bioavailability, and the apoptotic potential of these compounds highlights their therapeutic relevance. Overall, the pursuit of dual HDAC inhibitors reflects a paradigm shift in cancer treatment, emphasizing the necessity of comprehensive strategies to effectively combat the complexity of cancer biology [ 39 , 40 ]. Therefore, much effort is needed to develop novel and potent HDAC-based hybrid drugs [ 41 – 43 ].…”

Understanding Cancer’s Defense against Topoisomerase-Active Drugs: A Comprehensive Review

“…The idea to develop small-molecule agents that can work as dual inhibitors of both HDAC and TOPI/TOPII has been explored [249][250][251][252][253][254][255][256][257]. Kim et al have also emphasized the importance of dual targeting by the combinatorial treatment of CI-994, an HDAC inhibitor, with VP-16, leading to synergistic anticancer effects through Topo II and Ac-H3 regulation [258].…”

“…Modification leading to hypomethylation can either increase or decrease the sensitivity of cells to topoisomerase inhibitors due to altered mechanisms. Also, it has been reported that the dysregulation of histone acetyltransferase (HAT) and histone deacetylases (HDACC), which play a key role in regulating the level of acetylation in histone proteins, results in resistance against topoisomerase inhibitors (Figure 4) [12,[248][249][250][251][252][253][254][255][256][257][258][259][260].…”