Based on the lead compounds 1 and 2, a series of novel BACE1 inhibitors were designed and synthesized,among which compound 9h exhibited a 60 fold improvement in potency over the lead compound 1. This represents a good...Based on the lead compounds 1 and 2, a series of novel BACE1 inhibitors were designed and synthesized,among which compound 9h exhibited a 60 fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD. The result also showed that the prop-2-yn-1-yloxy is a suitable fragment for modification of cyclic acylguanidine BACE1 inhibitors.展开更多
Generation of multi-substituted pyrroles is accomplished through an unexpected iron(Ⅱ)-promoted reaction of N-arylprop-2-yn-1-imines with wate r.This transformation proceeds smoothly with excellent chemoselectivityan...Generation of multi-substituted pyrroles is accomplished through an unexpected iron(Ⅱ)-promoted reaction of N-arylprop-2-yn-1-imines with wate r.This transformation proceeds smoothly with excellent chemoselectivityand regioselectivity.A stoichiometric amount of Fe(OTf)_(2) is necessary for the succes s ful conversion.A Lewis acid-promoted tandem reaction pathway is proposed.展开更多
目的研究厚朴抗炎有效成分(E)-5-allyl-3'-(prop-1-enyl)biphenyl-2,4'-diol(HK-1)在人、大鼠、比格犬、猴和小鼠的肝微粒体中的代谢稳定性,确定HK-1在大鼠肝微粒体中代谢表型。方法将HK-1在5个种属肝微粒体中孵育,采用UPLC-MS...目的研究厚朴抗炎有效成分(E)-5-allyl-3'-(prop-1-enyl)biphenyl-2,4'-diol(HK-1)在人、大鼠、比格犬、猴和小鼠的肝微粒体中的代谢稳定性,确定HK-1在大鼠肝微粒体中代谢表型。方法将HK-1在5个种属肝微粒体中孵育,采用UPLC-MS/MS检测方法,通过测定HK-1的剩余浓度,考察它们的代谢稳定性并外推其体内代谢清除率。化学抑制剂法鉴定在大鼠肝微粒体中HK-1的代谢表型。结果 HK-1在人、大鼠、比格犬、猴和小鼠5个种属肝微粒体中半衰期(t_(1/2))分别为9.04、7.36、2.17、4.94、18.09 min;肝微粒体中固有清除率CL_(int)分别为153.40、188.20、639.02、280.60、76.60 m L/(min·mg蛋白);体内固有清除率CL'_(int)分别为151.87、338.76、949.21、416.69、301.61 m L/(min·kg)。在大鼠肝微粒体中HK-1主要被细胞色素CYP2E1、CYP2C、CYP1A2催化代谢。结论HK-1在肝微粒体中由多种酶代谢且代谢很快,其中人肝微粒体和大鼠肝微粒体中半衰期和固有清除率相似,可将大鼠肝微粒体预估人肝微粒体不良反应的风险。展开更多
Objective:To isolate and characterize the cytotoxic compounds from Diospyros quercina(Baill.)G.E.Schatz&Lowry(Ebenaceae).Methods:An ethno-botanical survey was conducted in the south of Madagascar from July to Augu...Objective:To isolate and characterize the cytotoxic compounds from Diospyros quercina(Baill.)G.E.Schatz&Lowry(Ebenaceae).Methods:An ethno-botanical survey was conducted in the south of Madagascar from July to August 2010.Bio-guided fractionation assay was carried out on the root bark of Diospyros quercina,using cytotoxicity bioassay on murine P388 leukemia cell lines as model.The structures of the cytotoxic compounds were elucidated by 1D and 2D NMR spectroscopy and mass spectrometry.Results:Biological experiments resulted in the isolation of three bioactive pure compounds(named TR-21,TR-22,and TR-23)which exhibited very good in vitro cytotoxic activities with the IC_(50)values of(0.017 5±0.0060)μg/mL,(0.089±0.005)μg/mL and(1.027±0.070)μg/mL respectively.Thus,they support the claims of traditional healers and suggest the possible correlation between the chemical composition of this plant and its wide use in Malagasy folk medicine to treat cancer.Conclusions:The ability of isolated compounds in this study to inhibit cell growth may represent a rational explanation for the use of Diospyros quercina root bark in treating cancer by Malagasy traditional healers.Further studies are,therefore,necessary to evaluate the in vivo antineoplastic activity of these cytotoxic compounds as effective anticancer drugs.展开更多
基金supported by grants from The National Natural Science Foundation of China (No. 81172924)Beijing Municipal Natural Science Foundation (No. 7112106)
文摘Based on the lead compounds 1 and 2, a series of novel BACE1 inhibitors were designed and synthesized,among which compound 9h exhibited a 60 fold improvement in potency over the lead compound 1. This represents a good lead for the discovery of more promising BACE1 inhibitors for the potential treatment of AD. The result also showed that the prop-2-yn-1-yloxy is a suitable fragment for modification of cyclic acylguanidine BACE1 inhibitors.
基金Financial support from the National Natural Science Foundation of China(Nos.21871053 and 21532001)the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(No.2019R01005)is gratefully acknowledged。
文摘Generation of multi-substituted pyrroles is accomplished through an unexpected iron(Ⅱ)-promoted reaction of N-arylprop-2-yn-1-imines with wate r.This transformation proceeds smoothly with excellent chemoselectivityand regioselectivity.A stoichiometric amount of Fe(OTf)_(2) is necessary for the succes s ful conversion.A Lewis acid-promoted tandem reaction pathway is proposed.
文摘目的研究厚朴抗炎有效成分(E)-5-allyl-3'-(prop-1-enyl)biphenyl-2,4'-diol(HK-1)在人、大鼠、比格犬、猴和小鼠的肝微粒体中的代谢稳定性,确定HK-1在大鼠肝微粒体中代谢表型。方法将HK-1在5个种属肝微粒体中孵育,采用UPLC-MS/MS检测方法,通过测定HK-1的剩余浓度,考察它们的代谢稳定性并外推其体内代谢清除率。化学抑制剂法鉴定在大鼠肝微粒体中HK-1的代谢表型。结果 HK-1在人、大鼠、比格犬、猴和小鼠5个种属肝微粒体中半衰期(t_(1/2))分别为9.04、7.36、2.17、4.94、18.09 min;肝微粒体中固有清除率CL_(int)分别为153.40、188.20、639.02、280.60、76.60 m L/(min·mg蛋白);体内固有清除率CL'_(int)分别为151.87、338.76、949.21、416.69、301.61 m L/(min·kg)。在大鼠肝微粒体中HK-1主要被细胞色素CYP2E1、CYP2C、CYP1A2催化代谢。结论HK-1在肝微粒体中由多种酶代谢且代谢很快,其中人肝微粒体和大鼠肝微粒体中半衰期和固有清除率相似,可将大鼠肝微粒体预估人肝微粒体不良反应的风险。
基金Supported by the Third World Academy of Science.(TWAS Fellowship for Research and Advanced Training FR number:Grant No.3240224121the International Foundation for Science (IFS,Stockholm,Sweden) and the Organizationfor the Prohibition of Chemical Weapons(OPCW)(IFS Research Grant No F/4921-2)
文摘Objective:To isolate and characterize the cytotoxic compounds from Diospyros quercina(Baill.)G.E.Schatz&Lowry(Ebenaceae).Methods:An ethno-botanical survey was conducted in the south of Madagascar from July to August 2010.Bio-guided fractionation assay was carried out on the root bark of Diospyros quercina,using cytotoxicity bioassay on murine P388 leukemia cell lines as model.The structures of the cytotoxic compounds were elucidated by 1D and 2D NMR spectroscopy and mass spectrometry.Results:Biological experiments resulted in the isolation of three bioactive pure compounds(named TR-21,TR-22,and TR-23)which exhibited very good in vitro cytotoxic activities with the IC_(50)values of(0.017 5±0.0060)μg/mL,(0.089±0.005)μg/mL and(1.027±0.070)μg/mL respectively.Thus,they support the claims of traditional healers and suggest the possible correlation between the chemical composition of this plant and its wide use in Malagasy folk medicine to treat cancer.Conclusions:The ability of isolated compounds in this study to inhibit cell growth may represent a rational explanation for the use of Diospyros quercina root bark in treating cancer by Malagasy traditional healers.Further studies are,therefore,necessary to evaluate the in vivo antineoplastic activity of these cytotoxic compounds as effective anticancer drugs.
