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-r...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.展开更多
Breast cancer is one of the most common cancers and the leading cause of cancer-related deaths among women due to the diagnostic delay and failure of treatment.1 Despite the significant progress made in developing the...Breast cancer is one of the most common cancers and the leading cause of cancer-related deaths among women due to the diagnostic delay and failure of treatment.1 Despite the significant progress made in developing therapeutic strategies for breast cancer,effective treatment of breast cancer,particularly aggressive triple-negative breast cancer,remains lacking.Angiogenesis is a crucial risk factor for breast cancer metastasis and a predictor of poor prognosis.Thus,developing novel agents capable of suppressing tumor angiogenesis offers a promising approach for breast cancer treatment.Oridonin,the major active ingredient of the traditional Chinese medicinal herb,exhibits anti-cancer activity by inhibiting tumor-induced angiogenesis.2 Nevertheless,the therapeutic potential of oridonin is limited due to its rapid plasma clearance and limited potency.Various novel oridonin analogues have been designed and chemically synthesized by modifying their A,B,and D rings to achieve an agent with better anti-cancer efficacy and lower toxicity than oridonin.3 Chick embryo chorioallantoic membrane(CAM)and yolk sac membrane(YSM)models were commonly utilized to study tumor-induced angiogenesis.To discover the promising anti-angiogenic agents,we screened novel oridonin analogues synthesized in-house using the CAM and YSM models.展开更多
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...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.展开更多
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 i...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.展开更多
基金supported by the grant of Rangsit University to SJthe Chulalongkorn University Centenary Academic Development Project(CU56-FW10)+2 种基金National Research University Project(FW657B)to TAthe Thailand Research Fund(No.DBG5180014)the Center for Environmental Health,Toxicology and Management of Chemicals to PK
文摘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.
基金supported by the Basic and Applied Basic Research Project of Guangdong Province,China(No.2023A1515010459 to C.L.Q.)Key Team of Basic and Clinical Research on Tumor Immunotherapy of Guangdong Pharmaceutical University(No.2024ZZ10 to X.L.)+2 种基金the Project of Administration of Traditional Chinese Medicine of Guangdong Province,China(No.20251209 to C.L.Q.20242048 to P.T.)Dr.Jia Zhou has no connections with the above-mentioned funding resources in China,and is partly supported by the John D.Stobo,M.D.Distinguished Chair Endowment Fund,and Edith&Robert Zinn Chair in Drug Discovery Endowment Fund at the University of Texas Medical Branch in the United States.
文摘Breast cancer is one of the most common cancers and the leading cause of cancer-related deaths among women due to the diagnostic delay and failure of treatment.1 Despite the significant progress made in developing therapeutic strategies for breast cancer,effective treatment of breast cancer,particularly aggressive triple-negative breast cancer,remains lacking.Angiogenesis is a crucial risk factor for breast cancer metastasis and a predictor of poor prognosis.Thus,developing novel agents capable of suppressing tumor angiogenesis offers a promising approach for breast cancer treatment.Oridonin,the major active ingredient of the traditional Chinese medicinal herb,exhibits anti-cancer activity by inhibiting tumor-induced angiogenesis.2 Nevertheless,the therapeutic potential of oridonin is limited due to its rapid plasma clearance and limited potency.Various novel oridonin analogues have been designed and chemically synthesized by modifying their A,B,and D rings to achieve an agent with better anti-cancer efficacy and lower toxicity than oridonin.3 Chick embryo chorioallantoic membrane(CAM)and yolk sac membrane(YSM)models were commonly utilized to study tumor-induced angiogenesis.To discover the promising anti-angiogenic agents,we screened novel oridonin analogues synthesized in-house using the CAM and YSM models.
基金Work in the David lab is supported by R21 DA044767,CCSG core grant P30 CA008748,and SPORE P50-CA192937 from the National Institutes of Health.In addition,work in the lab is supported by the Tri-institutional Therapeutic Discovery Institute,the Mr.William H.Goodwin and Mrs.Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Center for Experimental Therapeutics at MSKCC,the Pershing Square Sohn Cancer Research Alliance,and Cycle for Survival.Y.D.is a Josie Robertson Young Investigator.Additionally,YD is supported by the Parker Institute for Cancer Immunotherapy and the Anna Fuller Cancer Research Foundation.
文摘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.
基金This study was partially supported by grants AI131669,AI140726,and AI141178 from the National Institute of Allergy and Infectious Diseases(NIAID,USA)the National Institutes of Health(Hongmin Li and Jia Zhou)+2 种基金Additionally,Jia Zhou is partly supported by the John D.Stobo,M.D.Distinguished Chair Endowment Fund at UTMBHongmin Li is additionally supported by NIH grants AI133219,AI134568,AI140406,and AI140491,USAthe R.Ken and Donna Coit Endowed Chair fund in Drug Discovery.
文摘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.
