Structure−Activity Relationship Studies of a Series of Novel δ-Lactam-Based Histone Deacetylase Inhibitors

We synthesized a series of δ-lactam-based HDAC inhibitors that were identified with various degrees of anti-inflammatory and cell growth inhibitory activities. Compounds possessing significant HDAC inhibitory activity exhibited both anti-inflammatory and cell growth inhibitory activities as well as significant tumor growth inhibition in the in vivo tumor xenograft experiments. Besides, these compounds demonstrated anti-inflammatory properties in vitro via suppression of the production of the proinflammatory cytokine TNF-α and nitric oxide by LPS-stimulated RAW264.7 cells

Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a γ-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability

Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a γ-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability