A new approach for asymmetric synthesis of alkannin and shikonin is presented. The chiral centers of the targets were introduced via an asymmetric C-arylation of protected chiral glyceraldehyde in high de. The two e...A new approach for asymmetric synthesis of alkannin and shikonin is presented. The chiral centers of the targets were introduced via an asymmetric C-arylation of protected chiral glyceraldehyde in high de. The two enantiomers were prepared with the D-isopropylidenegly- ceraldehyde as the starting material.展开更多
Based on the asymmetric reduction of alkannin ketone derivative 4 by diisopinocampheylchloro- borane（DIP-C1）, a series of shikonin and alkannin derivatives was designed, synthesized and their anticancer activi- ties...Based on the asymmetric reduction of alkannin ketone derivative 4 by diisopinocampheylchloro- borane（DIP-C1）, a series of shikonin and alkannin derivatives was designed, synthesized and their anticancer activi- ties against various kinds of cell lines were evaluated. The in vitro biological experiments demonstrated that com- pound S-10, a 5,8-O-dimethyl-l,4-dioxime alkannin derivative, not only displayed excellent antiproliferative activity against cancer cells, but also exhibited 10w toxicity towards normal cells. It could induce HCT-116 cell apoptosis, but had no impact on the cell cycle. The underlying anticancer mechanism of S-10 is most likely different from other shikonin and alkannin derivatives.展开更多
Alkannin/shikonin(A/S)and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants.They are integral constituents of traditional Chinese medicine Zicao(roots of Lithospermu...Alkannin/shikonin(A/S)and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants.They are integral constituents of traditional Chinese medicine Zicao(roots of Lithospermum erythrorhizon).In last two decades significant increase in pharmacological investigations on alkannin/shikonin and their derivatives has been reported that resulted in discovery of their novel mechanisms in various diseases and disorders.This review throws light on recently conducted pharmacological investigations on alkannin/shikonin and their derivatives and their outputs.Various analytical aspects are also discussed and brief summary of patent applications on inventions containing alkannin/shikonin and its derivatives is also provided.展开更多
DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colore...DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colorectal carcinoma and melanoma.However,its potent cytotoxicity is not closely associated with reactive oxygen species（ROS） and bioreductive alkylation.Its specific antitumor target（s） has still remained elusive.To recognize the molecular target（s） of DMAKO-05 and its analogs,four biotinylated DMAKO derivatives were designed and prepared.The biotin moiety was successfully introduced in the molecule through a modified Mitsunobu reaction,which kept its anticancer activity.Moreover,the cellbased investigation demonstrated that replacement of the linker C4 chain with another alkyl chain（C6 or C8） gave rise to the enhancement of cytotoxicity.Among these biotinyl derivatives,both compound 16 and 8c exhibited more potent anticancer activity than DMAKO-05 against MCF-7 cells and were comparatively effective to alkannin toward HCT-15 cells.As expected,they might be thought as ideal chemical probes.Collectively,our present work could provide an available approach for the identification of the potential antineoplastic target（s） of DMAKO derivatives.展开更多
The aim of this study was to investigate the potential of novel electrospun fiber mats loaded with alkannin and shikonin(A/S)derivatives,using as carrier a highly biocompatible,bio-derived,ecofriendly polymer such as ...The aim of this study was to investigate the potential of novel electrospun fiber mats loaded with alkannin and shikonin(A/S)derivatives,using as carrier a highly biocompatible,bio-derived,ecofriendly polymer such as poly[(R)-3-hydroxybutyric acid](PHB).PHB fibers containing a mixture of A/S derivatives at different ratios were successfully fabricated via electrospinning.As evidenced by scanning electron microscopy,the fibers formed a bead-free mesh with average diameters from 1.25 to 1.47 lm.Spectroscopic measurements suggest that electrospinning marginally increases the amorphous content of the predominantly crystalline PHB in the fibers,while a significant drug amount lies near the fiber surface for samples of high total A/S content.All scaffolds displayed satisfactory characteristics,with the lower concentrations of A/S mixture-loaded PHB fiber mats achieving higher porosity,water uptake ratios,and entrapment efficiencies.The in vitro dissolution studies revealed that all samples released more than 70%of the encapsulated drug after 72 h.All PHB scaffolds tested by cell viability assay were proven non-toxic for Hs27 fibroblasts,with the 0.15 wt.%sample favoring cell attachment,spreading onto the scaffold surface,as well as cell proliferation.Finally,the antimicrobial activity of PHB meshes loaded with A/S mixture was documented for Staphylococcus epidermidis and S.aureus.展开更多
目的利用药物化学中的拼合原理将替尼类抗肿瘤药物利尼伐尼与紫草素通过不同长度的碳链进行偶联,设计合成一系列结构新颖的紫草素-利尼伐尼衍生物。方法用核磁共振氢谱(nuclear magnetic resonance hydrogen spectrum,^(1)H-NMR)、核磁...目的利用药物化学中的拼合原理将替尼类抗肿瘤药物利尼伐尼与紫草素通过不同长度的碳链进行偶联,设计合成一系列结构新颖的紫草素-利尼伐尼衍生物。方法用核磁共振氢谱(nuclear magnetic resonance hydrogen spectrum,^(1)H-NMR)、核磁共振碳谱(nuclear magnetic resonance carbon spectrum,^(13)C-NMR)和高分辨质谱(high resolution mass spectrometry,HRMS)对衍生物的结构进行确认;用HepG2、A549和HCT-116肿瘤细胞系和L02肝正常细胞系对衍生物的抗肿瘤活性和细胞毒选择性进行评价;用4’,6-二脒基-2-苯基吲哚(4,6-diamidino-2-phenylindole,DAPI)、吉姆萨(Giemsa)染色和流式细胞术分析优势衍生物对细胞凋亡的影响;用细胞划痕实验和鹌鹑胚绒毛尿囊膜(quail chick chorioallantoic membrane,qCAM)模型评价衍生物对细胞迁移和血管生成的影响。结果衍生物AL-8对肝癌细胞HepG2表现出较好的增殖抑制活性[IC_(50)=(1.53±0.39)μmol·L^(-1)],其活性优于前体药物利尼伐尼[IC_(50)=(4.93±0.62)μmol·L^(-1)]和紫草素[IC_(50)=(1.91±0.17)μmol·L^(-1)],而对肝正常细胞系L02的毒性较小。作用机制研究结果表明,其能显著诱导肿瘤细胞凋亡,抑制肿瘤细胞迁移和血管新生。结论筛选得到高效、低毒的衍生物AL-8,为紫草素-利尼伐尼抗肿瘤衍生物的发现提供参考。展开更多
基金the National Natural Science Foundation of China[32071532]for financial supports
文摘A new approach for asymmetric synthesis of alkannin and shikonin is presented. The chiral centers of the targets were introduced via an asymmetric C-arylation of protected chiral glyceraldehyde in high de. The two enantiomers were prepared with the D-isopropylidenegly- ceraldehyde as the starting material.
基金the National Natural Science Foundation of China（No.81373274） and the State Key Laboratory Cultivatlon Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China （No.CHEMR2012-B08）.
文摘Based on the asymmetric reduction of alkannin ketone derivative 4 by diisopinocampheylchloro- borane（DIP-C1）, a series of shikonin and alkannin derivatives was designed, synthesized and their anticancer activi- ties against various kinds of cell lines were evaluated. The in vitro biological experiments demonstrated that com- pound S-10, a 5,8-O-dimethyl-l,4-dioxime alkannin derivative, not only displayed excellent antiproliferative activity against cancer cells, but also exhibited 10w toxicity towards normal cells. It could induce HCT-116 cell apoptosis, but had no impact on the cell cycle. The underlying anticancer mechanism of S-10 is most likely different from other shikonin and alkannin derivatives.
文摘Alkannin/shikonin(A/S)and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants.They are integral constituents of traditional Chinese medicine Zicao(roots of Lithospermum erythrorhizon).In last two decades significant increase in pharmacological investigations on alkannin/shikonin and their derivatives has been reported that resulted in discovery of their novel mechanisms in various diseases and disorders.This review throws light on recently conducted pharmacological investigations on alkannin/shikonin and their derivatives and their outputs.Various analytical aspects are also discussed and brief summary of patent applications on inventions containing alkannin/shikonin and its derivatives is also provided.
基金supported by National Natural Science Foundation of China (No. 81373274)Ph.D. Programs Foundation of Ministry of Education China (No. 20120073110068)Shanghai Biomedical Supporting Funding (No. 15431900600)
文摘DMAKO-05,a novel dimethylation of alkannin oxime derivative,exhibits remarkable anticancer activity as well as excellent cellular selectivity and thus has been considered as a promising antineoplastic agent for colorectal carcinoma and melanoma.However,its potent cytotoxicity is not closely associated with reactive oxygen species（ROS） and bioreductive alkylation.Its specific antitumor target（s） has still remained elusive.To recognize the molecular target（s） of DMAKO-05 and its analogs,four biotinylated DMAKO derivatives were designed and prepared.The biotin moiety was successfully introduced in the molecule through a modified Mitsunobu reaction,which kept its anticancer activity.Moreover,the cellbased investigation demonstrated that replacement of the linker C4 chain with another alkyl chain（C6 or C8） gave rise to the enhancement of cytotoxicity.Among these biotinyl derivatives,both compound 16 and 8c exhibited more potent anticancer activity than DMAKO-05 against MCF-7 cells and were comparatively effective to alkannin toward HCT-15 cells.As expected,they might be thought as ideal chemical probes.Collectively,our present work could provide an available approach for the identification of the potential antineoplastic target（s） of DMAKO derivatives.
基金This work was supported by the project‘MICROMETABOLITE’that has received funding from the European Union’s Horizon 2020 research and innovation programme,under the Marie Skłodowska-Curie grant agreement[No 721635]A.S.Arampatzis,K.N.Kontogiannopoulos,A.Rat,A.Willems and A.N.Assimopoulou acknowledge support of this work from MICROMETABOLITE.
文摘The aim of this study was to investigate the potential of novel electrospun fiber mats loaded with alkannin and shikonin(A/S)derivatives,using as carrier a highly biocompatible,bio-derived,ecofriendly polymer such as poly[(R)-3-hydroxybutyric acid](PHB).PHB fibers containing a mixture of A/S derivatives at different ratios were successfully fabricated via electrospinning.As evidenced by scanning electron microscopy,the fibers formed a bead-free mesh with average diameters from 1.25 to 1.47 lm.Spectroscopic measurements suggest that electrospinning marginally increases the amorphous content of the predominantly crystalline PHB in the fibers,while a significant drug amount lies near the fiber surface for samples of high total A/S content.All scaffolds displayed satisfactory characteristics,with the lower concentrations of A/S mixture-loaded PHB fiber mats achieving higher porosity,water uptake ratios,and entrapment efficiencies.The in vitro dissolution studies revealed that all samples released more than 70%of the encapsulated drug after 72 h.All PHB scaffolds tested by cell viability assay were proven non-toxic for Hs27 fibroblasts,with the 0.15 wt.%sample favoring cell attachment,spreading onto the scaffold surface,as well as cell proliferation.Finally,the antimicrobial activity of PHB meshes loaded with A/S mixture was documented for Staphylococcus epidermidis and S.aureus.
文摘目的利用药物化学中的拼合原理将替尼类抗肿瘤药物利尼伐尼与紫草素通过不同长度的碳链进行偶联,设计合成一系列结构新颖的紫草素-利尼伐尼衍生物。方法用核磁共振氢谱(nuclear magnetic resonance hydrogen spectrum,^(1)H-NMR)、核磁共振碳谱(nuclear magnetic resonance carbon spectrum,^(13)C-NMR)和高分辨质谱(high resolution mass spectrometry,HRMS)对衍生物的结构进行确认;用HepG2、A549和HCT-116肿瘤细胞系和L02肝正常细胞系对衍生物的抗肿瘤活性和细胞毒选择性进行评价;用4’,6-二脒基-2-苯基吲哚(4,6-diamidino-2-phenylindole,DAPI)、吉姆萨(Giemsa)染色和流式细胞术分析优势衍生物对细胞凋亡的影响;用细胞划痕实验和鹌鹑胚绒毛尿囊膜(quail chick chorioallantoic membrane,qCAM)模型评价衍生物对细胞迁移和血管生成的影响。结果衍生物AL-8对肝癌细胞HepG2表现出较好的增殖抑制活性[IC_(50)=(1.53±0.39)μmol·L^(-1)],其活性优于前体药物利尼伐尼[IC_(50)=(4.93±0.62)μmol·L^(-1)]和紫草素[IC_(50)=(1.91±0.17)μmol·L^(-1)],而对肝正常细胞系L02的毒性较小。作用机制研究结果表明,其能显著诱导肿瘤细胞凋亡,抑制肿瘤细胞迁移和血管新生。结论筛选得到高效、低毒的衍生物AL-8,为紫草素-利尼伐尼抗肿瘤衍生物的发现提供参考。
