1291075-53-0

Upstream product

• 928775-87-5 1-tert-butyl-4-(2-iodoethyl)benzene 
• 5621-44-3 dimethyl 2-methylenepentanedioate 
• 1258215-83-6 N-(4-tert-butylphenethyl)but-3-en-1-amine 
• 93633-32-0 5-methoxy-2-methylene-5-oxopentanoic acid 
• 1291073-22-7 methyl 4-(but-3-enyl(4-tert-butylphenethyl)carbamoyl)pent-4-enoate 

Downstream Products

• 1258215-59-6 3-(1-(4-tert-butylphenethyl)-2-oxo-1,2,5,6-tetrahydropyridin-3-yl)-N-hydroxypropanamide 

Relevant academic research and scientific papers

Lactam-based HDAC inhibitors for anticancer chemotherapy: Restoration of RUNX3 by posttranslational modification and epigenetic control

Expression and stability of the tumor suppressor runt-related transcription factora 3 (RUNX3) are regulated by histone deacetylase (HDAC). HDAC inhibition alters epigenetic and posttranslational stability of RUNX3, leading to tumor suppression. However, HDAC inhibitors can nonselectively alter global gene expression through chromatin remodeling. Thus, lactam-based HDAC inhibitors were screened to identify potent protein stabilizers that maintain RUNX3 stability by acetylation. RUNX activity and HDAC inhibition were determined for 111 lactam-based analogues through a cell-based RUNX activation and HDAC inhibition assay. 3-[1-(4-Bromobenzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-N- hydroxypropanamide (11-8) significantly increased RUNX3 acetylation and stability with relatively low RUNX3 mRNA expression and HDAC inhibitory activity. This compound showed significant antitumor effects, which were stronger than SAHA, in an MKN28 xenograft model. Thus, we propose a novel strategy, in which HDAC inhibitors serve as antitumor chemotherapeutic agents that selectively target epigenetic regulation and protein stability of RUNX3.

Property based optimization of δ-lactam HDAC inhibitors for metabolic stability

The novel δ-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and δ-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability.