A Potent HDAC Inhibitor, 1-Alaninechlamydocin, from a Tolypocladium sp Induces G2/M Cell Cycle Arrest and Apoptosis in MIA PaCa-2 Cells

作者：Du Lin; Risinger April L; King Jarrod B; Powell Douglas R; Cichewicz Robert H^*

来源：Journal of Natural Products, 2014, 77(7): 1753-1757.

DOI：10.1021/np500387h

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 (H-1-H-1 ROESY, ECD, and X-ray diffraction) and chemical (Marfey%26apos;s analysis) methods. 1-Alaninechlamydocin showed potent antiproliferative/cytotoxic activities in a human pancreatic cancer cell line (MIA PaCa-2) at low-nanomolar concentrations (GI(50) 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.

• 出版日期2014-7