2. Academic Validation
  3. Synthesis and bioactivity evaluation of ferrocene-based hydroxamic acids as selective histone deacetylase 6 inhibitors

Synthesis and bioactivity evaluation of ferrocene-based hydroxamic acids as selective histone deacetylase 6 inhibitors

  • Eur J Med Chem. 2023 Jan 15;246:115004. doi: 10.1016/j.ejmech.2022.115004.
Jiangkun Yan 1,  Kairui Yue 1,  Xuejing Fan 1,  Ximing Xu 2,  Jing Wang 1,  Mengting Qin 3,  Qianer Zhang 1,  Xiaohan Hou 1,  Xiaoyang Li 4,  Yong Wang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 26003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266200, PR China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 26003, Shandong, PR China; Marine Biomedical Research Institute of Qingdao, Qingdao, Shandong, 266071, PR China.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 26003, Shandong, PR China.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 26003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266200, PR China. Electronic address: [email protected].
  • 5 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 26003, Shandong, PR China; Laboratory for Marine Drugs and Bioproducts, Center for Innovation Marine Drug Screening & Evaluation, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266200, PR China. Electronic address: [email protected].
PMID: 36516583 DOI: 10.1016/j.ejmech.2022.115004
Abstract

Histone deacetylase 6 (HDAC6) is involved in multiple regulatory processes and emerges as a promising target for treating Cancer and neurodegenerative diseases. Benefited from the unique sandwich conformation of ferrocene, a series of ferrocene-based hydroxamic acids have been developed as novel HDAC6 inhibitors in this paper, especially the two ansa-ferrocenyl complexes with IC50s at the nanomolar level. [3]-Ferrocenophane hydroxamic acid analog II-5 displays the most potent inhibitory activity on HDAC6 and establishes remarkable selectivity towards other HDAC isoforms. Compound II-5 dose-dependently induces accumulation of acetylated α-tubulin while having a negligible effect on the level of acetylated Histone H3, confirming its isoform selectivity. Further biological evaluation of II-5 on Cancer cells corroborates its antiproliferative effect, which mainly contributed to the induction of cellular Apoptosis. It is worth noting that compound II-5 demonstrates an optimal profile on human plasma stability. These results strengthen ferrocene's unique role in developing selective protein inhibitors and indicate that compound II-5 may be a suitable lead for further evaluation and development for treating HDAC6-associated disorders and diseases.

Keywords

Anticancer agents; Apoptosis; Bioorganometallic chemistry; Ferrocenophane; HDAC.

Figures
Products