Background: Mitochondrial dysfunction is a key event mediating mutant Htt-induced neurotoxicity. Results: trans-(Ϫ)-⑀-Viniferin attenuates mutantHtt-induced SIRT3 depletion, activates AMPK, and preserves mitochondrial function. Conclusion: Increasing SIRT3 protects cells in HD.Significance: The result suggests a promising new target for development of HD therapeutics.

Chemical epigenetic manipulation of Penicillium citreonigrum led to profound changes in the secondary metabolite profile of its guttate. While guttate from control cultures exhibited a relatively simple assemblage of secondary metabolites, the guttate collected from cultures treated with 50 μM 5-azacytidine (a DNA methyltransferase inhibitor) were highly enriched in compounds representing at least three distinct biosynthetic families. The metabolites obtained from the fungus included six azaphilones (sclerotiorin (1), sclerotioramine (6), ochrephilone (2), dechloroisochromophilone III (3), dechloroisochromophilone IV (4), and 6-((3E,5E)-5,7-dimethyl-2-methylenenona-3,5-dienyl)-2,4-dihydroxy-3-methylbenzaldehyde (5)), pencolide (7), and two new meroterpenes (atlantinones A and B (9 and 10, respectively)). While pencolide was detected in the exudates of both control and 5-azacytidine-treated cultures, all of the other natural products were found exclusively in the guttates of the epigenetically modified fungus. All of the metabolites from the P. citreonigrum guttate were tested for antimicrobial activity in a disk diffusion assay. Both sclerotiorin and sclerotioramine caused modest inhibition of Staphylococcus epidermidis growth; however, only sclerotioramine was active against a panel of Candida strains.Our research group has been actively pursuing the development of chemical epigenetic methods for procuring secondary metabolites from fungi. 1 We have demonstrated that this is an effective technique for promoting the transcription of silent biosynthetic pathways involved in the formation of polyketide, non-ribosomal peptide, and hybrid polyketide-non-ribosomalpeptide natural products. 2 Moreover, we have shown that a chemical epigenetics approach is well suited for the generation of structurally unique secondary metabolites with promising drug discovery applications. 3,4 In order to maximize the opportunity for detecting novel secondary metabolites, we have begun using chemical epigenetic induction as a routine part of our screening program involving the exploration of fungi obtained from minimally explored environments/ecological niches (e.g., insects and littoral zones4).* To whom correspondence should be addressed. Tel: (405) 325-6969. rhcichewicz@ou.edu.. † Natural Products Discovery Group, Department of Chemistry and Biochemistry. ‡ Current address: Empresa Brasileira de Pesquisa Agropecuária-EMBRAPA, Coastal Tablelands, Av. Beira Mar, 3250, 49025-040, Aracaju, SE, Brazil. § Department of Chemistry and Biochemistry. ⊥ Ecology and Evolutionary Biology Program.Supporting Information Available: NMR ( 1 H and 13 C NMR, HSQC, HMBC, COSY, and ROESY) data for compounds 6, 7, 9, and 10 and 1 H NMR and 1D difference NOE data for 8 are provided. This information is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Nat Prod. Author manuscript; available in PMC 2011 May 28. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptOur investiga...

This work has demonstrated that a previously unexplored approach to separation of enantiomers via formation of diastereomeric derivatives with three stereogenic centers has obvious practical potential and deserves further systematic study. The design reported here is based on the unusual application of a configurationally unstable stereogenic nitrogen, which plays a key role in setting up the stereochemical match between the three stereogenic centers in the corresponding products.

A synthetically practical and operationally convenient method for preparing (S)-2-[N-(N'-benzylprolyl)amino]benzophenone (BPBP) and hitherto unknown (S)-2-[N-(N'-benzylprolyl)amino]-4-methylbenzophenone (4-Me-BPBP), (S)-2-[N-(N'-benzylprolyl)amino]-5-nitrobenzophenone (5-NO(2)-BPBP), and their corresponding Ni(II) complexes with glycine [GlyNi(II)BPBP], a widely used chiral equivalent of nucleophilic glycine, and new analogues [GlyNi(II)-4-Me-BPBP] and [GlyNi(II)-5- NO(2)-BPBP] is described. The key step of the method is the synthetically efficient amid bond formation between the corresponding o-aminobenzophenones, featuring significant steric shielding and low nucleophilicity of the amino functionality as well as sterically constrained (S)-N-benzylproline (BP).