Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases

J Enzyme Inhib Med Chem. 2024 Dec;39(1):2406025. doi: 10.1080/14756366.2024.2406025. Epub 2024 Sep 24.

Abstract

Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.

Keywords: Class IIa histone deacetylases (HDACs); cancer cells; molecular modelling; structure-activity relationship (SAR).

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Dose-Response Relationship, Drug*
  • Drug Screening Assays, Antitumor*
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Histone Deacetylases* / metabolism
  • Humans
  • Hydroxamic Acids* / chemical synthesis
  • Hydroxamic Acids* / chemistry
  • Hydroxamic Acids* / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Phenothiazines* / chemical synthesis
  • Phenothiazines* / chemistry
  • Phenothiazines* / pharmacology
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Histone Deacetylases
  • Antineoplastic Agents
  • Phenothiazines
  • phenothiazine

Grants and funding

This work was supported by the National Science and Technology Council (MOST111-2320-B-038–042-MY3 and MOST110-2320-B-038–024-MY3) in Taiwan.