title: Synthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222.
abstract: In the course of our ongoing efforts to discover new and more effective HDAC inhibitors useful for the development of promising anticancer candidates, we have recently undertaken a molecular modelling study on a small collection of FR235222 analogues, synthesized by us in the frame of a structure-activity relationship investigation, made in order to identify the key structural elements essential for the activity. Progress made in structure elucidation of HDAC active site, together with accurate docking calculations, provided new structural insights useful for a further refinement of the tetrapeptide scaffold which should assure an optimal interaction between the synthetic ligands and the biological target. Following the computer aided suggestions we synthesized six new cyclotetrapeptide analogues of the lead compound (3-8), bearing a carboxylic or an hydroxamic acid functionality as Zn binding moiety. Herein we describe their synthesis and their inhibition activity on different HDAC isoforms.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Terracciano
authors.forename: Simone
authors.initials: S
authors.lastname: Di Micco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Paola
authors.initials: P
authors.lastname: Gallinari
authors.forename: Raffaele
authors.initials: R
authors.lastname: Riccio
authors.forename: Ines
authors.initials: I
authors.lastname: Bruno
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003198:Computer Simulation; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C474179:FR 235222; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D020033:Protein Isoforms; C534894:azumamide E; D006655:Histone Deacetylases