Synthesis and Biological Evaluation of Novel 2-Aroyl Benzofuran-Based Hydroxamic Acids as Antimicrotubule Agents

• Published in: International journal of molecular sciences 2024-07, Vol.25 (14), p.7519
• Main Authors: Mariotto, Elena, Canton, Martina, Marchioro, Chiara, Brancale, Andrea, Hamel, Ernest, Varani, Katia, Vincenzi, Fabrizio, De Ventura, Tiziano, Padroni, Chiara, Viola, Giampietro, Romagnoli, Romeo
• Format: Article
• Language: English
• Subjects: Analysis; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Benzofurans - chemical synthesis; Benzofurans - chemistry; Benzofurans - pharmacology; Binding sites; Cancer; Cancer therapies; Care and treatment; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Combination therapy; Drug discovery; Drug resistance; Drug Screening Assays, Antitumor; Enzymes; FDA approval; HeLa Cells; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; HT29 Cells; Humans; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Kinases; Lymphoma; MCF-7 Cells; Polymerization; Proteins; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tubulins; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25147519

Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a -hydroxyacrylamide or a -hydroxypropiolamide at the 5-position of the 2-aroylbenzo[ ]furan skeleton, to produce compounds - and - , respectively. Among the synthesized compounds, derivatives , , , , and showed excellent antiproliferative activity, with IC values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds and were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that - , , , , and , although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.