Natural products are the important source for the discovery of more potent anti-HIV agents.In this study,six daphnane diterpenoids including three unreported structures were isolated from Trigonostemon lii,which showe...Natural products are the important source for the discovery of more potent anti-HIV agents.In this study,six daphnane diterpenoids including three unreported structures were isolated from Trigonostemon lii,which showed signifcant activities against HIV-1 strains replication in the nanomolar/picomolar range.Meanwhile,these diterpenoids signifcantly inhibited the fusion of H9/HIV-1 IIIB cells with uninfected C8166 cells,with the EC50s from 1.06 to 8.73 ng/mL,and did not show any inhibition activities against HIV-1 reverse transcriptase.Moreover,all of the diterpenoids shows signifcant inhibitions against T20-resistan HIV-1 strains,PNL4-3gp41(36G)V38E,N42S and pNL4-3gp41(36G)V38A,N42T.The results revealed that the six diterpenoids could be a new type of potential lead candidate as an HIV entry inhibitor,particularly for those infected by T20-resistant variants.展开更多
A new daphnane diterpene was isolated from the root barks of Daphne tangutica Maxim. Its structure was elucidated as 1, 2α-dihydro-20-palimoyldaphnctoxin by the spectroscopic evidence including 2D-NMR.
Thirteen novel diterpenoids,comprising seven tiglianes(walliglianes G−M,1−7),four rhamnofolanes(wallinofolanes A−D,8−11),and two daphnanes(wallaphnanes A and B,12 and 13),together with two known rhamnofolane diterpeno...Thirteen novel diterpenoids,comprising seven tiglianes(walliglianes G−M,1−7),four rhamnofolanes(wallinofolanes A−D,8−11),and two daphnanes(wallaphnanes A and B,12 and 13),together with two known rhamnofolane diterpenoids(euphorwallside H and euphorwallside I,14 and 15),were isolated and characterized from Euphorbia wallichii(E.wallichii).The chemical structures of these compounds were elucidated through nuclear magnetic resonance(NMR),mass spectrometry(MS),and quantum chemical calculations.Compounds 9 and 11 demonstrated protective effects against H2O2-induced BV-2 microglial cell damage.Molecular docking analyses indicated that compound 9 exhibited binding affinity to the anti-oxidant-related targets HMGCR,GSTP1,and SHBG.展开更多
AIM： To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder （Thymelaeaceae）. METHOD： The anti-HIV activities of wikstroelide M against differ...AIM： To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder （Thymelaeaceae）. METHOD： The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking. RESULTS： Wikstroelide M potently inhibited different HIV-1 strains, including HIV-lmn, HIV-1AI7, and HIV-19495, induced a cytopathic effect, with ECs0 values ranging from 3.81 to 15.65 ng.mL-I. Wikstroelide M also had high inhibitory activities against HIV-2noD and HIV-2cBL_20-induced cytopathic effects with ECs0 values of 18.88 and 31.90 ng.mL 1. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with ECs0 values ranging from 15.16 to 35.57 ng.mL-1. Wikstroelide M also potently inhibited HIV-lnm induced cytolysis in MT-4 cells, with an ECs0 value of 9.60 ng.mL ~. The mechanistic assay showed that wikstroelide M targeted HIV-I reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75. CONCLUSION： Wikslroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear Iranslocation through dismpting the interaction between integrase and LEDGF/p75.展开更多
Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers.However,the lack of druggable inhibitors restricts its therapeutic proof of concept.In the present work,...Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers.However,the lack of druggable inhibitors restricts its therapeutic proof of concept.In the present work,we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability(>25 folds)and oral bioavailability.DD1-Br inhibited the survival of castration-resistant prostate cancer(CRPC)cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy(0.5 mg/kg)and in enzalutamidecombination therapy.Mechanistic study revealed that by targeting importin-β1,DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers,particularly AR-V7,a main contributor to enzalutamide resistance,leading to the integral suppression of downstream oncogenic signaling.This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.展开更多
A practical approach to the asymmetric synthesis of the ring A substructure of genkwadane A, a daphnane diterpenoid, was developed. This synthesis features the Mukaiyama aldol reaction to introduce the quaternary ster...A practical approach to the asymmetric synthesis of the ring A substructure of genkwadane A, a daphnane diterpenoid, was developed. This synthesis features the Mukaiyama aldol reaction to introduce the quaternary stereogenic center at C4 and VO（acac）2-catalyzed Jackson-Ellman-Bolrn sulfoxidation to deliver the corresponding sulfoxide. The Dieckmann-type condensation was efficiently promoted by KHMDS and the ring A substructure was finally accomplished through Barton iodination condition.展开更多
基金supported financially by grants from the National Science Foundation of China(21432010 and 81660612)Technological leading talent project of Yunnan(2015HA020)+1 种基金Yunnan Applied Basic Research Project-Kunming Medical University Union Foundation(2017FE467(-127),Scientific Research Fund Projects from the Department of Education of Yunnan(2016ZDX042)the Hundred-Talent Program of Kunming Medical University(60117190441).
文摘Natural products are the important source for the discovery of more potent anti-HIV agents.In this study,six daphnane diterpenoids including three unreported structures were isolated from Trigonostemon lii,which showed signifcant activities against HIV-1 strains replication in the nanomolar/picomolar range.Meanwhile,these diterpenoids signifcantly inhibited the fusion of H9/HIV-1 IIIB cells with uninfected C8166 cells,with the EC50s from 1.06 to 8.73 ng/mL,and did not show any inhibition activities against HIV-1 reverse transcriptase.Moreover,all of the diterpenoids shows signifcant inhibitions against T20-resistan HIV-1 strains,PNL4-3gp41(36G)V38E,N42S and pNL4-3gp41(36G)V38A,N42T.The results revealed that the six diterpenoids could be a new type of potential lead candidate as an HIV entry inhibitor,particularly for those infected by T20-resistant variants.
文摘A new daphnane diterpene was isolated from the root barks of Daphne tangutica Maxim. Its structure was elucidated as 1, 2α-dihydro-20-palimoyldaphnctoxin by the spectroscopic evidence including 2D-NMR.
基金supported by the National Natural Science Foundation of China(Nos.82405016 and 82141216)the Project of Frontier Technology Platform for Research Projects of Liaoning Provincial Department of Education in 2024(No.LJ232410163056)+3 种基金"Select the best candidates to lead key research projects"of Fujian University of Traditional Chinese Medicine(Nos.XJB2022008 and XJB2023001)the Foundation of Fujian University of Traditional Chinese Medicine(Nos.X2023001-Talent and X2024002-Talent)the Young and Middle-aged Teacher Education Research Project in Fujian Province(No.JZ230023)the Central Government Guides Local Science and Technology Development Fund Projects(No.2023L3014).
文摘Thirteen novel diterpenoids,comprising seven tiglianes(walliglianes G−M,1−7),four rhamnofolanes(wallinofolanes A−D,8−11),and two daphnanes(wallaphnanes A and B,12 and 13),together with two known rhamnofolane diterpenoids(euphorwallside H and euphorwallside I,14 and 15),were isolated and characterized from Euphorbia wallichii(E.wallichii).The chemical structures of these compounds were elucidated through nuclear magnetic resonance(NMR),mass spectrometry(MS),and quantum chemical calculations.Compounds 9 and 11 demonstrated protective effects against H2O2-induced BV-2 microglial cell damage.Molecular docking analyses indicated that compound 9 exhibited binding affinity to the anti-oxidant-related targets HMGCR,GSTP1,and SHBG.
基金supported,in part,by grants from the National Natural Science Foundation of China(Nos.81102483,81001462)the 973 Program(No.2009CB522306)the Key Scientific and Technological Program of China(Nos.2009-ZX09501-029,2012ZX10001-006,2012ZX10001-007,2012ZX-09103-101-022),and Yunnan(No.2010GA001)
文摘AIM： To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder （Thymelaeaceae）. METHOD： The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking. RESULTS： Wikstroelide M potently inhibited different HIV-1 strains, including HIV-lmn, HIV-1AI7, and HIV-19495, induced a cytopathic effect, with ECs0 values ranging from 3.81 to 15.65 ng.mL-I. Wikstroelide M also had high inhibitory activities against HIV-2noD and HIV-2cBL_20-induced cytopathic effects with ECs0 values of 18.88 and 31.90 ng.mL 1. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with ECs0 values ranging from 15.16 to 35.57 ng.mL-1. Wikstroelide M also potently inhibited HIV-lnm induced cytolysis in MT-4 cells, with an ECs0 value of 9.60 ng.mL ~. The mechanistic assay showed that wikstroelide M targeted HIV-I reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75. CONCLUSION： Wikslroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear Iranslocation through dismpting the interaction between integrase and LEDGF/p75.
基金supported by the Natural Science Foundation of China(Nos.82273804,81973195,81872891,and 81973203)the Southerm Marine Science and Engineering Guangdong Laboratory(Zhuhai)(No.SML2021SP301,China)+2 种基金Open Program of Shenzhen Bay Laboratory(No.SZBL2021080601007,China)the Guangdong Natural Science Funds for Distinguished Young Scholar(No.2019B151502016,China)Guangdong-Hong Kong-Macao research team project of the Guangdong Basic and Applied Basic Research Foundation(No.2022B1515130008,China).
文摘Nuclear transporter importin-β1 is emerging as an attractive target by virtue of its prevalence in many cancers.However,the lack of druggable inhibitors restricts its therapeutic proof of concept.In the present work,we optimized a natural importin-β1 inhibitor DD1 to afford an improved analog DD1-Br with better tolerability(>25 folds)and oral bioavailability.DD1-Br inhibited the survival of castration-resistant prostate cancer(CRPC)cells with sub-nanomolar potency and completely prevented tumor growth in resistant CRPC models both in monotherapy(0.5 mg/kg)and in enzalutamidecombination therapy.Mechanistic study revealed that by targeting importin-β1,DD1-Br markedly inhibited the nuclear accumulation of multiple CRPC drivers,particularly AR-V7,a main contributor to enzalutamide resistance,leading to the integral suppression of downstream oncogenic signaling.This study provides a promising lead for CRPC and demonstrates the potential of overcoming drug resistance in advanced CRPC via targeting importin-β1.
文摘A practical approach to the asymmetric synthesis of the ring A substructure of genkwadane A, a daphnane diterpenoid, was developed. This synthesis features the Mukaiyama aldol reaction to introduce the quaternary stereogenic center at C4 and VO（acac）2-catalyzed Jackson-Ellman-Bolrn sulfoxidation to deliver the corresponding sulfoxide. The Dieckmann-type condensation was efficiently promoted by KHMDS and the ring A substructure was finally accomplished through Barton iodination condition.
