Synthesis and biological evaluation of histone deacetylase inhibitors that are based on FR235222: A cyclic tetrapeptide scaffold

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 8; pp. 2549 - 2554
• Main Authors: Singh, Erinprit K., Ravula, Suchitra, Pan, Chung-Mao, Pan, Po-Shen, Vasko, Robert C., Lapera, Stephanie A., Weerasinghe, Sujith V.W., Pflum, Mary Kay H., McAlpine, Shelli R.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-04-2008; Elsevier
• Subjects: Antineoplastic agents; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; FR235222; General aspects; Guanidine; HDAC; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Medical sciences; Molecular Structure; Pancreatic cancer; Peptide; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; FR235222; Peptide; Guanidine; Pancreatic cancer; HDAC; Human; Enzyme; Cyclic peptides; Enzyme inhibitor; Guanidines; Biological activity; Histone deacetylase inhibitor; Cell line; Tetrapeptide; Pancreas cancer; Hydrolases; Pancreas; Chemical synthesis; Tumor cell
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.03.047

We outline the synthesis of six novel derivatives that are based on a recently discovered HDAC inhibitor FR235222. Our work is the first report utilizing a novel binding element, guanidine, as metal coordinators in HDAC inhibitors. Further, we demonstrate that these compounds show cytotoxicity that parallels their ability to inhibit deacetylase activity, and that the most potent compounds maintain an
l-Phe at position 1, and a
d-Pro at position 4. Both inhibition of HDAC activity and cytotoxicity against the pancreatic cancer cell line BxPC3 are exhibited by these compounds, establishing that a guanidine unit can be utilized successfully to inhibit HDAC activity.