title: A potent HDAC inhibitor, 1-alaninechlamydocin, from a Tolypocladium sp. induces G2/M cell cycle arrest and apoptosis in MIA PaCa-2 cells.
abstract: The cyclic tetrapeptide 1-alaninechlamydocin was purified from a Great Lakes-derived fungal isolate identified as a Tolypocladium sp. Although the planar structure was previously described, a detailed analysis of its spectroscopic data and biological activity are reported here for the first time. Its absolute configuration was determined using a combination of spectroscopic ((1)H-(1)H ROESY, ECD, and X-ray diffraction) and chemical (Marfey's analysis) methods. 1-Alaninechlamydocin showed potent antiproliferative/cytotoxic activities in a human pancreatic cancer cell line (MIA PaCa-2) at low-nanomolar concentrations (GI50 5.3 nM, TGI 8.8 nM, LC50 22 nM). Further analysis revealed that 1-alaninechlamydocin induced G2/M cell cycle arrest and apoptosis. Similar to other cyclic epoxytetrapeptides, the inhibitory effects of 1-alaninechlamydocin are proposed to be produced primarily via inhibition of histone deacetylase (HDAC) activity.
authors.affiliation: Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, ‡Natural Products Discovery Group, and Institute for Natural Products Applications and Research Technologies, University of Oklahoma , Norman, Oklahoma 73019-5251, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: April L
authors.initials: AL
authors.lastname: Risinger
authors.forename: Jarrod B
authors.initials: JB
authors.lastname: King
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Powell
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cichewicz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010190:Pancreatic Neoplasms; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*
chemical_list: C000591564:1-alaninechlamydocin; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic