Novel (E)‐3‐(3‐Oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis and Bioevaluation

• Published in: Chemistry & biodiversity Vol. 20; no. 5; pp. e202201030 - n/a
• Main Authors: Minh Sang, Doan, Ho Na, Ik, Tien Anh, Duong, Thi Mai Dung, Do, Thi Thu Hang, Nguyen, Phuong‐Anh, Nguyen T., Hai, Pham‐The, Thi Kim Oanh, Dao, Thanh Tung, Truong, Jung Lee, Soo, Hee Kwon, Joo, Soon Kang, Jong, Han, Sang‐Bae, Thi Thanh Hai, Dinh, Nam, Nguyen‐Hai
• Format: Journal Article
• Language: English
• Published: Switzerland Wiley Subscription Services, Inc 01-05-2023
• Subjects: Anticancer properties; Antineoplastic Agents - chemistry; Antitumor activity; Apoptosis; Assaying; benzoxazine; Cancer; Cell cycle; Cell Line, Tumor; Cell Proliferation; Cytotoxicity; docking simulation; Drug Design; Drug Screening Assays, Antitumor; Histone deacetylase; Histone deacetylase (HDAC) inhibitors; Histone Deacetylase Inhibitors - chemistry; Histones; Humans; Hydroxamic Acids; hydroxypropenamides; Inhibitors; Isoforms; Lung cancer; Molecular Docking Simulation; Prostate cancer; Structure-Activity Relationship; Substitutes; Synthesis; Toxicity testing; Tumor cell lines; Histone deacetylase (HDAC) inhibitors; benzoxazine; hydroxypropenamides; hydroxamic acids; docking simulation
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.202201030

Herein, we report the design, synthesis and evaluation of novel (E)‐3‐(3‐oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides (4 a–i, 7 a–g) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC‐3, prostate; NCI−H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a–i bearing the alkyl substituents seemed to be less potent than the benzyl‐containing compounds 7 a–g in all biological assays. Compounds 7 e–f were found to be the most active HDAC inhibitors with IC50 of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.