The Experts below are selected from a list of 1569 Experts worldwide ranked by ideXlab platform
Sulong Xiao - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure activity relationship and in vitro anti influenza virus activity of novel polyphenol Pentacyclic Triterpene conjugates
European Journal of Medicinal Chemistry, 2019Co-Authors: Shouxin Wang, Sulong Xiao, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Abstract It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain Pentacyclic Triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified Pentacyclic Triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 μM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 μM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.
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synthesis of novel Pentacyclic Triterpene neu5ac2en derivatives and investigation of their in vitro anti influenza entry activity
MedChemComm, 2017Co-Authors: Yongying Shi, Yongmin Zhang, Demin Zhou, Xu Han, Shouxin Wang, Zibo Fan, Jiaqi Sun, Sulong XiaoAbstract:Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived Pentacyclic Triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two Pentacyclic Triterpene-sialic acid conjugates under Zemplen conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type Triterpenes, oleanane-type Triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.
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inhibition of influenza virus infection by multivalent Pentacyclic Triterpene functionalized per o methylated cyclodextrin conjugates
European Journal of Medicinal Chemistry, 2017Co-Authors: Zhenyu Tian, Xiaoshu Zhou, Yongmin Zhang, Demin Zhou, Kun Meng, Sulong XiaoAbstract:Multivalent ligands that exhibit high binding affinity to influenza hemagglutinin (HA) trimer can block the interaction of HA with its sialic acid receptor. In this study, a series of multivalent Pentacyclic Triterpene-functionalized per-O-methylated cyclodextrin (CD) derivatives were designed and synthesized using 1, 3-dipolar cycloaddition click reaction. A cell-based assay showed that three compounds (25, 28 and 31) exhibited strong inhibitory activity against influenza A/WSN/33 (H1N1) virus. Compound 28 showed the most potent anti-influenza activity with IC50 of 4.7 μM. The time-of-addition assay indicated that compound 28 inhibited the entry of influenza virus into host cell. Further hemagglutination inhibition (HI) and surface plasmon resonance (SPR) assays indicated that compound 28 tightly bound to influenza HA protein with a dissociation constant (KD) of 4.0 μM. Our results demonstrated a strategy of using per-O-methylated β-CD as a scaffold for designing multivalent compounds to disrupt influenza HA protein-host receptor protein interaction and thus block influenza virus entry into host cells.
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synthesis and biological evaluation of novel Pentacyclic Triterpene α cyclodextrin conjugates as hcv entry inhibitors
European Journal of Medicinal Chemistry, 2016Co-Authors: Sulong Xiao, Qi Wang, Xiaoshu Zhou, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Hepatitis C virus (HCV) entry is a key target for the treatment of chronic HCV infection. In our continuing efforts to identify novel potential anti-HCV entry inhibitors, a series of water-soluble triazole-bridged α-cyclodextrin-Pentacyclic Triterpene conjugates were easily synthesized with moderate to good yields. These novel compounds were fully identified and characterized by 1D and 2D NMR spectroscopy and ESI-HRMS. The anti-HCV entry activities were determined based on HCVpp/VSVGpp entry assays. The best results were found for compounds 15 and 18, which displayed the most promising anti-HCV entry activities with average IC50 values of 1.18 μM and 0.25 μM, respectively. In addition, the in vitro cytotoxicity activity of the two compounds against MDCK cells showed no toxicity at 100 μM. Five different binding assays were set up to identify the action mechanism. The results showed that the compounds exert their inhibitory activity at the post-binding step and subsequently prevent virus entry.
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recent progresses on Pentacyclic Triterpene based antiviral agents
SCIENTIA SINICA Chimica, 2015Co-Authors: Sulong Xiao, Qi Wang, Lihe Zhang, Han Wang, Xu Han, Kun Meng, Zhenyu Tian, Demin ZhouAbstract:Pentacyclic Triterpenes are a class of secondary plant metabolites widely distributed throughout the plant kingdom with promising pharmacological activities including antitumor, anti-infection, immunomodulatory and so on. This review will focus on the anti-viral aspect of Pentacyclic Triterpene together with their derivatives and analogs on HIV, HCV and influenza viruses. This will be valuable for the development of novel Pentacyclic Triterpene-based antiviral therapeutic agents.
Yongmin Zhang - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure activity relationship and in vitro anti influenza virus activity of novel polyphenol Pentacyclic Triterpene conjugates
European Journal of Medicinal Chemistry, 2019Co-Authors: Shouxin Wang, Sulong Xiao, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Abstract It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain Pentacyclic Triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified Pentacyclic Triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 μM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 μM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.
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synthesis of novel Pentacyclic Triterpene neu5ac2en derivatives and investigation of their in vitro anti influenza entry activity
MedChemComm, 2017Co-Authors: Yongying Shi, Yongmin Zhang, Demin Zhou, Xu Han, Shouxin Wang, Zibo Fan, Jiaqi Sun, Sulong XiaoAbstract:Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived Pentacyclic Triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two Pentacyclic Triterpene-sialic acid conjugates under Zemplen conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type Triterpenes, oleanane-type Triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.
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inhibition of influenza virus infection by multivalent Pentacyclic Triterpene functionalized per o methylated cyclodextrin conjugates
European Journal of Medicinal Chemistry, 2017Co-Authors: Zhenyu Tian, Xiaoshu Zhou, Yongmin Zhang, Demin Zhou, Kun Meng, Sulong XiaoAbstract:Multivalent ligands that exhibit high binding affinity to influenza hemagglutinin (HA) trimer can block the interaction of HA with its sialic acid receptor. In this study, a series of multivalent Pentacyclic Triterpene-functionalized per-O-methylated cyclodextrin (CD) derivatives were designed and synthesized using 1, 3-dipolar cycloaddition click reaction. A cell-based assay showed that three compounds (25, 28 and 31) exhibited strong inhibitory activity against influenza A/WSN/33 (H1N1) virus. Compound 28 showed the most potent anti-influenza activity with IC50 of 4.7 μM. The time-of-addition assay indicated that compound 28 inhibited the entry of influenza virus into host cell. Further hemagglutination inhibition (HI) and surface plasmon resonance (SPR) assays indicated that compound 28 tightly bound to influenza HA protein with a dissociation constant (KD) of 4.0 μM. Our results demonstrated a strategy of using per-O-methylated β-CD as a scaffold for designing multivalent compounds to disrupt influenza HA protein-host receptor protein interaction and thus block influenza virus entry into host cells.
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synthesis and in vitro anti influenza virus evaluation of novel sialic acid c 5 and c 9 Pentacyclic Triterpene derivatives
Molecules, 2017Co-Authors: Xu Han, Zhenyu Tian, Yongying Shi, Shouxin Wang, Zibo Fan, Jiaqi Sun, Pingxuan Jiao, Fuxiang Ran, Yongmin ZhangAbstract:The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-Pentacyclic Triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with Pentacyclic Triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-Pentacyclic Triterpene conjugates. Their structures were confirmed by ESI-HRMS, ¹H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.
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synthesis and biological evaluation of novel Pentacyclic Triterpene α cyclodextrin conjugates as hcv entry inhibitors
European Journal of Medicinal Chemistry, 2016Co-Authors: Sulong Xiao, Qi Wang, Xiaoshu Zhou, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Hepatitis C virus (HCV) entry is a key target for the treatment of chronic HCV infection. In our continuing efforts to identify novel potential anti-HCV entry inhibitors, a series of water-soluble triazole-bridged α-cyclodextrin-Pentacyclic Triterpene conjugates were easily synthesized with moderate to good yields. These novel compounds were fully identified and characterized by 1D and 2D NMR spectroscopy and ESI-HRMS. The anti-HCV entry activities were determined based on HCVpp/VSVGpp entry assays. The best results were found for compounds 15 and 18, which displayed the most promising anti-HCV entry activities with average IC50 values of 1.18 μM and 0.25 μM, respectively. In addition, the in vitro cytotoxicity activity of the two compounds against MDCK cells showed no toxicity at 100 μM. Five different binding assays were set up to identify the action mechanism. The results showed that the compounds exert their inhibitory activity at the post-binding step and subsequently prevent virus entry.
Xu Han - One of the best experts on this subject based on the ideXlab platform.
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synthesis of novel Pentacyclic Triterpene neu5ac2en derivatives and investigation of their in vitro anti influenza entry activity
MedChemComm, 2017Co-Authors: Yongying Shi, Yongmin Zhang, Demin Zhou, Xu Han, Shouxin Wang, Zibo Fan, Jiaqi Sun, Sulong XiaoAbstract:Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived Pentacyclic Triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two Pentacyclic Triterpene-sialic acid conjugates under Zemplen conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type Triterpenes, oleanane-type Triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.
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synthesis and in vitro anti influenza virus evaluation of novel sialic acid c 5 and c 9 Pentacyclic Triterpene derivatives
Molecules, 2017Co-Authors: Xu Han, Zhenyu Tian, Yongying Shi, Shouxin Wang, Zibo Fan, Jiaqi Sun, Pingxuan Jiao, Fuxiang Ran, Yongmin ZhangAbstract:The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-Pentacyclic Triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with Pentacyclic Triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-Pentacyclic Triterpene conjugates. Their structures were confirmed by ESI-HRMS, ¹H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.
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Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives
MOLECULES, 2017Co-Authors: Xu Han, Zibo Fan, Si Long-long, Shi Yong-ying, Wang Shou-xin, Tian Zhen-yu, Li Man, Sun Jia-qi, Jiao Ping-xuan, Ran Fu-xiangAbstract:The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-Pentacyclic Triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with Pentacyclic Triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-Pentacyclic Triterpene conjugates. Their structures were confirmed by ESI-HRMS, H-1-NMR, and C-13-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 mu M. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 mu M (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 mu M, similar to 53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 mu M, similar to 20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.National Natural Science Foundation of China [81573269, 81373271, 21572015, 81361168002]SCI(E)ARTICLE72
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Synthesis of novel Pentacyclic Triterpene-Neu5Ac2en derivatives and investigation of their in vitro anti-influenza entry activity
MEDCHEMCOMM, 2017Co-Authors: Shi Yongying, Xu Han, Li Man, Si Longlong, Zhang Yongmin, Zhou Demin, Fan Zibo, Wang Shouxin, Sun Jiaqi, Xiao SulongAbstract:Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived Pentacyclic Triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two Pentacyclic Triterpene-sialic acid conjugates under ZemplEn conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane-and lupane-type Triterpenes, oleanane-type Triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 mu M) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.National Natural Science Foundation of China [81373271, 81361168002, 81573269, 21572015]SCI(E)ARTICLE71531-1541
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design synthesis and biological activity evaluation of novel conjugated sialic acid and Pentacyclic Triterpene derivatives as anti influenza entry inhibitors
MedChemComm, 2016Co-Authors: Xu Han, Xiaoshu Zhou, Han Wang, Kun Meng, Zhenyu Tian, Yongying Shi, Zibo Fan, Pingxuan Jiao, Hongwei Jin, Hong ChenAbstract:Influenza virus is a major human pathogen that causes annual epidemics and occasional pandemics. Recently, plant-derived Pentacyclic Triterpenes have been shown to act as highly potent anti-viral agents by efficiently preventing the attachment of the virion to the host cells. In this report, we conjugated sialic acid with oleanolic acid (OA), a natural product with broad antiviral entry activity, as well as three other analogs echinocystic acid (EA), ursolic acid (UA) and betulinic acid (BA). A total of 24 conjugated sialic acid and Pentacyclic Triterpene derivatives with different linkers were synthesized and evaluated for antiviral activity against influenza A/WSN/33 (H1N1) virus in MDCK cell culture. The most potent compound had an IC50 of 41.2 μM. Time-of-addition, hemagglutination inhibition (HI), surface plasmon resonance (SPR) and molecular docking assays demonstrated that compound 20a acted as an influenza virus entry inhibitor by preventing the binding of influenza virus hemagglutinin (HA) protein to host cells.
Demin Zhou - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure activity relationship and in vitro anti influenza virus activity of novel polyphenol Pentacyclic Triterpene conjugates
European Journal of Medicinal Chemistry, 2019Co-Authors: Shouxin Wang, Sulong Xiao, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Abstract It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain Pentacyclic Triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified Pentacyclic Triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 μM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 μM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.
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synthesis of novel Pentacyclic Triterpene neu5ac2en derivatives and investigation of their in vitro anti influenza entry activity
MedChemComm, 2017Co-Authors: Yongying Shi, Yongmin Zhang, Demin Zhou, Xu Han, Shouxin Wang, Zibo Fan, Jiaqi Sun, Sulong XiaoAbstract:Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived Pentacyclic Triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two Pentacyclic Triterpene-sialic acid conjugates under Zemplen conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type Triterpenes, oleanane-type Triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.
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inhibition of influenza virus infection by multivalent Pentacyclic Triterpene functionalized per o methylated cyclodextrin conjugates
European Journal of Medicinal Chemistry, 2017Co-Authors: Zhenyu Tian, Xiaoshu Zhou, Yongmin Zhang, Demin Zhou, Kun Meng, Sulong XiaoAbstract:Multivalent ligands that exhibit high binding affinity to influenza hemagglutinin (HA) trimer can block the interaction of HA with its sialic acid receptor. In this study, a series of multivalent Pentacyclic Triterpene-functionalized per-O-methylated cyclodextrin (CD) derivatives were designed and synthesized using 1, 3-dipolar cycloaddition click reaction. A cell-based assay showed that three compounds (25, 28 and 31) exhibited strong inhibitory activity against influenza A/WSN/33 (H1N1) virus. Compound 28 showed the most potent anti-influenza activity with IC50 of 4.7 μM. The time-of-addition assay indicated that compound 28 inhibited the entry of influenza virus into host cell. Further hemagglutination inhibition (HI) and surface plasmon resonance (SPR) assays indicated that compound 28 tightly bound to influenza HA protein with a dissociation constant (KD) of 4.0 μM. Our results demonstrated a strategy of using per-O-methylated β-CD as a scaffold for designing multivalent compounds to disrupt influenza HA protein-host receptor protein interaction and thus block influenza virus entry into host cells.
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synthesis and biological evaluation of novel Pentacyclic Triterpene α cyclodextrin conjugates as hcv entry inhibitors
European Journal of Medicinal Chemistry, 2016Co-Authors: Sulong Xiao, Qi Wang, Xiaoshu Zhou, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Hepatitis C virus (HCV) entry is a key target for the treatment of chronic HCV infection. In our continuing efforts to identify novel potential anti-HCV entry inhibitors, a series of water-soluble triazole-bridged α-cyclodextrin-Pentacyclic Triterpene conjugates were easily synthesized with moderate to good yields. These novel compounds were fully identified and characterized by 1D and 2D NMR spectroscopy and ESI-HRMS. The anti-HCV entry activities were determined based on HCVpp/VSVGpp entry assays. The best results were found for compounds 15 and 18, which displayed the most promising anti-HCV entry activities with average IC50 values of 1.18 μM and 0.25 μM, respectively. In addition, the in vitro cytotoxicity activity of the two compounds against MDCK cells showed no toxicity at 100 μM. Five different binding assays were set up to identify the action mechanism. The results showed that the compounds exert their inhibitory activity at the post-binding step and subsequently prevent virus entry.
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design synthesis and biological evaluation of novel l ascorbic acid conjugated Pentacyclic Triterpene derivatives as potential influenza virus entry inhibitors
European Journal of Medicinal Chemistry, 2016Co-Authors: Han Wang, Xiaoshu Zhou, Yongmin Zhang, Lihe Zhang, Xu Han, Yongying Shi, Zibo Fan, Pingxuan Jiao, Liangren Zhang, Demin ZhouAbstract:Since the influenza viruses can rapidly evolve, it is urgently required to develop novel anti-influenza agents possessing a novel mechanism of action. In our previous study, two Pentacyclic Triterpene derivatives (Q8 and Y3) have been found to have anti-influenza virus entry activities. Keeping the potential synergy of biological activity of Pentacyclic Triterpenes and l-ascorbic acid in mind, we synthesized a series of novel l-ascorbic acid-conjugated Pentacyclic Triterpene derivatives (18-26, 29-31, 35-40 and 42-43). Moreover, we evaluated these novel compounds for their anti-influenza activities against A/WSN/33 virus in MDCK cells. Among all evaluated compounds, the 2,3-O,O-dibenzyl-6-deoxy-l-ascorbic acid-betulinic acid conjugate (30) showed the most significant anti-influenza activity with an EC50 of 8.7 μM, and no cytotoxic effects on MDCK cells were observed. Time-of-addition assay indicated that compound 30 acted at an early stage of the influenza life cycle. Further analyses revealed that influenza virus-induced hemagglutination of chicken red blood cells was inhibited by treatment of compound 30, and the interaction between the influenza hemagglutinin (HA) and compound 30 was determined by surface plasmon resonance (SPR) with a dissociation constant of KD = 3.76 μM. Finally, silico docking studies indicated that compound 30 and its derivative 31 were able to occupy the binding pocket of HA for sialic acid receptor. Collectively, these results suggested that l-ascorbic acid-conjugated Pentacyclic Triterpenes were promising anti-influenza entry inhibitors, and HA protein associated with viral entry was a promising drug target.
Shouxin Wang - One of the best experts on this subject based on the ideXlab platform.
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synthesis structure activity relationship and in vitro anti influenza virus activity of novel polyphenol Pentacyclic Triterpene conjugates
European Journal of Medicinal Chemistry, 2019Co-Authors: Shouxin Wang, Sulong Xiao, Yongmin Zhang, Lihe Zhang, Demin ZhouAbstract:Abstract It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of influenza virus. Our earlier studies have identified that certain Pentacyclic Triterpene derivatives are effective inhibitors of influenza virus infection. In the present study, a series of C-28 modified Pentacyclic Triterpene derivatives via conjugation with a series of polyphenols were synthesized, and their antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 μM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 μM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.
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synthesis of novel Pentacyclic Triterpene neu5ac2en derivatives and investigation of their in vitro anti influenza entry activity
MedChemComm, 2017Co-Authors: Yongying Shi, Yongmin Zhang, Demin Zhou, Xu Han, Shouxin Wang, Zibo Fan, Jiaqi Sun, Sulong XiaoAbstract:Sialic acid derivatives, analogs, and their conjugates are important pharmacophores. Modification of the C-4 hydroxyl group of sialic acid can lead to derivatives, such as zanamivir, with potent anti-influenza activities. Herein, we described the synthesis of C-4-modified sialic acid derivatives via conjugation with naturally derived Pentacyclic Triterpenes, which are active ingredients of traditional Chinese medicine, and the evaluation of their in vitro anti-influenza virus activity in MDCK cells. Interestingly, a set of configurational isomers was obtained during the de-O-acetylation reaction of two Pentacyclic Triterpene-sialic acid conjugates under Zemplen conditions, and a mechanism was proposed. Owing to the attachment of the Neu5Ac2en moiety, all synthesized conjugates displayed lower hydrophobicity than their parent compounds. In comparison with ursane- and lupane-type Triterpenes, oleanane-type Triterpene-functionalized Neu5Ac2en conjugates were most promising. The insertion of a (1,2,3-triazol-4-yl)-methyl between the amide bond and Neu5Ac2en caused a substantial decrease in activity. Compound 15a exhibited the highest inhibitory activity (IC50 = 8.3 μM) and selectivity index (SI = 22.7). Further studies involving hemagglutination inhibition and neuraminidase inhibition suggested that compound 15a inhibited virus-induced hemagglutination with no effect on the enzymatic activity of neuraminidase, indicating that the antiviral activity appeared to be mediated via interaction with hemagglutinin at the initial stage of viral infection.
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synthesis and in vitro anti influenza virus evaluation of novel sialic acid c 5 and c 9 Pentacyclic Triterpene derivatives
Molecules, 2017Co-Authors: Xu Han, Zhenyu Tian, Yongying Shi, Shouxin Wang, Zibo Fan, Jiaqi Sun, Pingxuan Jiao, Fuxiang Ran, Yongmin ZhangAbstract:The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-Pentacyclic Triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with Pentacyclic Triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-Pentacyclic Triterpene conjugates. Their structures were confirmed by ESI-HRMS, ¹H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 μM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 μM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 μM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 μM, ~20-30%), and no significant anti-influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold.