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Updated: Sep 21, 2025
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy
Xuedong Li1, Xingang Liu2, Songsong Wang3
1School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China; Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.
Abstract:
The abnormal biological functions of HDAC6 were closely related to the occurrence and development of various tumors, making HDAC6 gradually become promising therapeutic target for cancer treatment and inspiring researchers to explore and develop selective HDAC inhibitors. In this study, based on the classical pharmacophore model of HDAC inhibitors, 20 compounds were designed and synthesized by modifying the Cap group, and the biological activities of the target compounds were assessed through anti-proliferation and enzyme inhibition experiments. The title compounds exhibited varying degrees of inhibitory activities against the selected tumor cell lines, especially the compounds 9m, 9q, and 12c, which were further evaluated at the enzymatic level. The enzyme inhibition assay showed that compound 12c exerted broad-spectrum enzyme inhibitory activities and compounds 9m and 9q were more inclined to inhibit HDAC6, exhibiting certain selective inhibitory activities among the representative subtypes. Moreover, the binding modes of compounds 9q and 12c in HDAC1&6 were further explored via computational approaches to elucidate the molecular mechanisms underlying selective inhibitory activities, providing valuable hints for the discovery of novel HDAC6 inhibitors.
Insights
Researchers designed and synthesized novel HDAC inhibitors to target cancer. Compounds 9m, 9q, and 12c showed significant anti-tumor activity, with 12c demonstrating broad-spectrum inhibition and 9m/9q selectively inhibiting HDAC6.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- Abnormal histone deacetylase 6 (HDAC6) function is linked to various cancers, positioning it as a key therapeutic target.
- Development of selective HDAC inhibitors is crucial for effective cancer treatment.
Purpose of the Study:
- To design and synthesize novel compounds targeting HDAC6 based on a pharmacophore model.
- To evaluate the anti-proliferative and enzyme inhibitory activities of synthesized compounds against cancer cells.
Main Methods:
- Design and synthesis of 20 novel compounds by modifying the cap group of known HDAC inhibitors.
- Assessment of biological activities through anti-proliferation assays on tumor cell lines.
- Enzymatic level evaluation and computational approaches to determine binding modes and mechanisms.
Main Results:
- Synthesized compounds displayed varying anti-proliferative effects on tested tumor cell lines.
- Compounds 9m, 9q, and 12c exhibited notable inhibitory activities.
- Compound 12c showed broad-spectrum enzyme inhibition, while 9m and 9q demonstrated selective inhibition of HDAC6.
Conclusions:
- Novel HDAC inhibitors were successfully synthesized and evaluated.
- Compounds 9m, 9q, and 12c represent promising leads for further development, particularly for HDAC6-targeted cancer therapy.
- Computational analysis provided insights into the molecular mechanisms of selective inhibition, aiding future drug design.
