Crystal Structure of 2-(2-Carboxy-4-hydroxy-6-methoxyphenoxy)-3,5-dichloro-6-hydroxy-4-methylbenzoic Acid 1-Methyl Ester

The title compound, neogeodin hydrate （C17H14C1208, CAS： 94540-50-8）, was derived from marine fungus Aspergilhts terreus CRIM301. It was unequivocally characterized by IR, NMR spectroscopies, and single-crystal X-ray crystallography and tested for various biological activities. Neogeodin hydrate crystallizes in the triclinic space group P1 with a = 8.1159（5） A, b = 8.2472（4） A, c= 14.1278（7） A, a = 81.448（2）°, β = 84.860（2）°, γ= 70.400（2）°, V = 880.13（8） A3; Z = 2. It comprises a diphenyl ether, asterric acid skeleton and dichloro substituents. The methoxyphenoxy rings of the inversely related molecules form a ribbon-like structure that is stabilized by O-H...O hydrogen bonds through the doubly disordered carboxyl groups and by C-H...O interactions, generating the same R22（8） ring motif. The chlorinated methylbenzoate rings, making mostly a right angle, link the parallel upper and lower ribbons via bifurcated O-H...O and C-H...O hydrogen bonds, yielding endless channels. The channels formed are further sustained by C-H...O and π...π interactions Neogeodin hydrate exhibits inhibition against superoxide anion radical formation in the xanthine/xanthine oxidase （XXO） assay, but has no aromatase inhibitory activity.

Non-enzymatic covalent modifications:a new link between metabolism and epigenetics

Epigenetic modifications,including those on DNA and histones,have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways.In turn,metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin modifications.Recently,non-enzymatic covalent modifications(NECMs)by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple mechanisms.Here,we summarize these recent advances in the identification and characterization of NECMs on nucleic acids,histones,and transcription factors,providing an additional mechanistic link between metabolism and epigenetics.

In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

Zika virus(ZIKV)causes significant human diseases without specific therapy.Previously we found erythrosin B,an FDA-approved food additive,inhibited viral NS2B−NS3 interactions,leading to inhibition of ZIKV infection in cell culture.In this study,we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse models.Our results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid model.Although pharmacokinetics studies indicated that erythrosin B had a low absorption profile,mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B,compared to vehicle control.Limited structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions,protease activity and antiviral efficacy.In contrast,introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities,suggesting that the isobenzofuran ring is well tolerated for modifications.Cytotoxicity studies indicated that all derivatives are nontoxic to human cells.Overall,our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.