Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation

• Published in: Pharmaceutics Vol. 14; no. 12; p. 2600
• Main Authors: Ruzic, Dusan, Ellinger, Bernhard, Djokovic, Nemanja, Santibanez, Juan F, Gul, Sheraz, Beljkas, Milan, Djuric, Ana, Ganesan, Arasu, Pavic, Aleksandar, Srdic-Rajic, Tatjana, Petkovic, Milos, Nikolic, Katarina
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25-11-2022; MDPI
• Subjects: 1-benzhydryl piperazine; Acids; Antimitotic agents; Antineoplastic agents; Breast cancer; Cell cycle; Chemical properties; Chemotherapy; Chromatography; Crystal structure; drug discovery; Enzyme inhibitors; Enzymes; Epigenetics; Gene expression; Health aspects; Heterocyclic compounds; histone deacetylases; Hydrocarbons; hydroxamic acid; Metastasis; NMR; Nuclear magnetic resonance; Pharmaceutical research; Potassium; zebrafish xenograft model; Zinc; Serbia; United States > US; drug discovery; anti-metastatic effect; breast cancer; histone deacetylases; hydroxamic acid; 1-benzhydryl piperazine; zebrafish xenograft model
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics14122600

Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC
values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.