title: Synthesis and biological evaluation of histone deacetylase inhibitors that are based on FR235222: a cyclic tetrapeptide scaffold.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, 5500 Campanile Drive, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Erinprit K
authors.initials: EK
authors.lastname: Singh
authors.forename: Suchitra
authors.initials: S
authors.lastname: Ravula
authors.forename: Chung-Mao
authors.initials: CM
authors.lastname: Pan
authors.forename: Po-Shen
authors.initials: PS
authors.lastname: Pan
authors.forename: Robert C
authors.initials: RC
authors.lastname: Vasko
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Lapera
authors.forename: Sujith V W
authors.initials: SV
authors.lastname: Weerasinghe
authors.forename: Mary Kay H
authors.initials: MK
authors.lastname: Pflum
authors.forename: Shelli R
authors.initials: SR
authors.lastname: McAlpine
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; C474179:FR 235222; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C102351:apicidin; D006655:Histone Deacetylases