Synthesis and Structure–Activity Relationship of 3‑Hydroxypyridine-2-thione-Based Histone Deacetylase Inhibitors

• Published in: Journal of medicinal chemistry 2013-12, Vol.56 (24), p.9969-9981
• Main Authors: Sodji, Quaovi H, Patil, Vishal, Kornacki, James R, Mrksich, Milan, Oyelere, Adegboyega K
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Chlorocebus aethiops; 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; Jurkat Cells; Models, Molecular; Molecular Structure; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship; Thiones - chemical synthesis; Thiones - chemistry; Thiones - pharmacology; Vero Cells
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401225q

We previously identified 3-hydroxypyridine-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure–activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but devoid of HDAC1 inhibition. To delineate further the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds, 10d and 14e, with potent HDAC6 and HDAC8 activities that are inactive against HDAC1. These new HDACi possess anticancer activities against various cancer cell lines including Jurkat J.γ1 for which SAHA and the previously disclosed 3HPT-derived HDACi were inactive.