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

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2014-07, Vol.77 (7), p.1753-1757
• Main Authors: Du, Lin, Risinger, April L, King, Jarrod B, Powell, Douglas R, Cichewicz, Robert H
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Cell Cycle - drug effects; G2 Phase - drug effects; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - isolation & purification; Histone Deacetylase Inhibitors - pharmacology; Humans; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pancreatic Neoplasms; Peptides, Cyclic - chemistry; Peptides, Cyclic - isolation & purification; Peptides, Cyclic - pharmacology
• ISSN: 0163-3864; 1520-6025
• 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 (1H–1H 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.