JOURNAL OF THE CHINESE CHEMICAL SOCIETY
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2019
·Vol. 67
·期 4
·646-651
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IF 1.188
Chun-Mei Liu,Xiao-Yan Tian,Chun-Hua Su,Jia-Yan Huang,Xiang-Wu Chu,Sheng-Ping Deng,Ke-Guang Cheng
To discover novel nitrogen mustards, the reported mustard pharmacophore was combined with natural pentacyclic triterpenes, which are characterized with pharmacological and structural diversity. Thus, six conjugates were synthesized with 1,2,3-triazole linking N , N -bis (2-chloroethyl)-1,4-phenylenediamine and oleanolic acid, ursolic acid, or glycyrrhetinic acid, and their biological activity was evaluated against tumor cell lines HeLa, BGC-823, BEL-7404, and NCI-H460 using the MTT assay. As a result, these conjugates showed some selective cytotoxicity to NCI-H460, though all their activity potency was moderate or weak in the four cell lines.
研究领域:
药物化学
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肿瘤学
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有机合成
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DOI
高影响因子
BIOMATERIALS
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2015
·
IF 8.557
Sulong Xiao,Longlong Si,Zhenyu Tian,Pingxuan Jiao,Zibo Fan,Kun Meng,Xiaoshu Zhou,Han Wang,Renyang Xu,Xu Han,Ge Fu,Yongmin Zhang,Lihe Zhang,Demin Zhou
Multivalent effect plays an important role in biological processes , particularly in the specific recognition of virus with its host cell during the first step of infection. Here we report the synthesis of multivalent pentacyclic triterpene grafted on cyclodextrin core and potency of against influenza entry activity. Nine star-shaped compounds containing six, seven and eight pentacyclic triterpene pharmacophore on cyclodextrin scaffold were prepared by way of copper-catalyzed azide-alkyl cycloaddition reaction under microwave activation. Some of the multimers exhibited much potent antiviral activity against H1N1 virus (A/WSN/33), even equivalent or superior to oseltamivir . The most active compound 31 , a heptavalent oleanolic acid- β -cyclodextrin conjugate , shows an up to 125-fold potency enhancement by its IC 50 value over the corresponding monovalent conjugate and oleanolic acid, disclosing a clear multivalent effect. Further studies show that three compounds 31 – 33 exhibited broad spectrum inhibitory activity against other two human influenza A/JX/312 (H3N2) and A/HN/1222 (H3N2) viruses with the IC 50 values at 2.47–14.90 μ M. Most importantly, we found that compound 31, one of the best representative conjugate, binds tightly to the viral envelope hemagglutinin with a dissociation constant of K D = 2.08 μ M, disrupting the interaction of hemagglutinin with the sialic acid receptor and thus the attachment of viruses to host cells. Our study might establish a strategy for the design of new pharmaceutical agents based on multivalency so as to block influenza virus entry into host cells.
研究领域:
药理学
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病毒学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY OF NATURAL COMPOUNDS
·
2018
·Vol. 54
·期 1
·106-111
·
IF 0.45
Huang Jia-yan,Yang Lin-dong,Su Chun-hua,Chu Xiang-wu,Zhang Jiang-yu,Deng Sheng-ping,Cheng Ke-guang
Using a reported pharmacophore, 4-[N,N-bis(2-chloroethyl)-amino]phenol, and pentacyclic triterpenes, pharmacologically and structurally diverse components of natural products, six pentacyclic triterpene-4-[N,N-bis(2-chloroethyl)-amino]phenol conjugates were synthesized by click chemistry. Their cytotoxicities against the BEL-7404 and NCI-H460 tumor cell lines were evaluated by the MTT assay. The in vitro results from the cytotoxicity assay indicated that at a compound concentration of 20 μM, these conjugates showed low toxicity (< 16%) toward the tested tumor cells in culture.
研究领域:
药理学
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肿瘤学
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有机化学
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DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Yuan Zhu,Xiaoguang Yan,Weiguo Li,Jianjun Qiao,Guang-Rong Zhao
Ursolic acid, a plant-derived pentacyclic triterpenoid with anti-inflammatory, antioxidant, and other bioactive properties, holds significant potential for use in nutritional supplements and drug development. However, its extraction from medicinal plants is inefficient due to low yield and dependence on seasonality and geography. Herein, we use modular metabolic engineering to enhance ursolic acid production in Saccharomyces cerevisiae by dividing the biosynthetic pathway into five modules. First, the heterologous ursolic acid biosynthesis module was established using Catharanthus roseus α-amyrin synthase (CrMAS) and a fused α-amyrin oxidase (CrOAS) with cytochrome P450 reductase (CPR). Next, the full hybrid mevalonate pathway was overexpressed, and the copy number of CrMAS was optimized. The sterol pathway was further optimized by introducing N-degron tags to relieve the competition pathway and deleting the SSM4 gene to enhance the ERG1 stability. Acetyl-CoA supply was improved via phosphoketolase and acetyl-CoA synthase pathways, combined with fine-tuning of mitochondrial and cytosolic carbon flux. The final engineered strain produced 1083.62 mg/L of ursolic acid in shake-flask cultures and 8.59 g/L in a 5 L bioreactor via fed-batch fermentation, achieving the highest microbial ursolic acid titer reported to date. This study not only demonstrates the potential for efficient biosynthesis of triterpenoid compounds but also provides ideas that can be extended to other microbial hosts for the concentrated use of intracellular carbon sources in the synthesis of complex natural products.
研究领域:
代谢工程
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生物技术
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生物化学
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微生物生物技术
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产品关联
DOI
PubMed
高影响因子
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