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

Autor: Hsu KC; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan., Huang YY; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan., Chu JC; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan., Huang YW; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan., Hu JL; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan., Lin TE; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan., Yen SC; Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China., Weng JR; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan., Huang WJ; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.; School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Jazyk: angličtina
Zdroj: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2024 Dec; Vol. 39 (1), pp. 2406025. Date of Electronic Publication: 2024 Sep 24.
DOI: 10.1080/14756366.2024.2406025
Abstrakt: 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 IC 50 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.
Databáze: MEDLINE