2. Academic Validation
  3. Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy

Design, Synthesis, and biological evaluation of HDAC6 inhibitors based on Cap modification strategy

  • Bioorg Chem. 2022 Aug;125:105874. doi: 10.1016/j.bioorg.2022.105874.
Xuedong Li 1,  Xingang Liu 2,  Songsong Wang 3,  Xiaoxing Shi 2,  Ming Lu 4,  Xinyue Hao 2,  Yan Fu 5,  Yang Zhang 6,  Qingzhong Jia 7,  Dian He 8
Affiliations

Affiliations

  • 1 School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China; Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China.
  • 2 School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China; Departments of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
  • 3 School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China; Departments of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China; The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
  • 4 The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China.
  • 5 School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China.
  • 6 School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China; Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: [email protected].
  • 7 School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China; Departments of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China; Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: [email protected].
  • 8 Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou 730000, China. Electronic address: [email protected].
PMID: 35636097 DOI: 10.1016/j.bioorg.2022.105874
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.

Keywords

4-anilinoquinazoline; Anti-proliferation; Molecular docking; Molecular dynamic simulation; Selective HDAC6 inhibitors.

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