Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors
Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ...
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Gespeichert in:
| Autor*in: |
Dinh, Chau Phi [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020transfer abstract |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles - Jose, Ajay ELSEVIER, 2018, Amsterdam [u.a.] |
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| Übergeordnetes Werk: |
volume:202 ; year:2020 ; day:15 ; month:09 ; pages:0 |
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| DOI / URN: |
10.1016/j.ejmech.2020.112518 |
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| 520 | |a Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. | ||
| 520 | |a Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. | ||
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10.1016/j.ejmech.2020.112518 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001104.pica (DE-627)ELV051059916 (ELSEVIER)S0223-5234(20)30490-6 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Dinh, Chau Phi verfasserin aut Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors 2020transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Vitamin E Elsevier Leukotrienes Elsevier 5-Lipoxygenase Elsevier Inflammation Elsevier Semi-synthesis Elsevier Molecular docking Elsevier Ville, Alexia oth Neukirch, Konstantin oth Viault, Guillaume oth Temml, Veronika oth Koeberle, Andreas oth Werz, Oliver oth Schuster, Daniela oth Stuppner, Hermann oth Richomme, Pascal oth Helesbeux, Jean-Jacques oth Séraphin, Denis oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:202 year:2020 day:15 month:09 pages:0 https://doi.org/10.1016/j.ejmech.2020.112518 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 202 2020 15 0915 0 |
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10.1016/j.ejmech.2020.112518 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001104.pica (DE-627)ELV051059916 (ELSEVIER)S0223-5234(20)30490-6 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Dinh, Chau Phi verfasserin aut Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors 2020transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Vitamin E Elsevier Leukotrienes Elsevier 5-Lipoxygenase Elsevier Inflammation Elsevier Semi-synthesis Elsevier Molecular docking Elsevier Ville, Alexia oth Neukirch, Konstantin oth Viault, Guillaume oth Temml, Veronika oth Koeberle, Andreas oth Werz, Oliver oth Schuster, Daniela oth Stuppner, Hermann oth Richomme, Pascal oth Helesbeux, Jean-Jacques oth Séraphin, Denis oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:202 year:2020 day:15 month:09 pages:0 https://doi.org/10.1016/j.ejmech.2020.112518 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 202 2020 15 0915 0 |
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10.1016/j.ejmech.2020.112518 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001104.pica (DE-627)ELV051059916 (ELSEVIER)S0223-5234(20)30490-6 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Dinh, Chau Phi verfasserin aut Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors 2020transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Vitamin E Elsevier Leukotrienes Elsevier 5-Lipoxygenase Elsevier Inflammation Elsevier Semi-synthesis Elsevier Molecular docking Elsevier Ville, Alexia oth Neukirch, Konstantin oth Viault, Guillaume oth Temml, Veronika oth Koeberle, Andreas oth Werz, Oliver oth Schuster, Daniela oth Stuppner, Hermann oth Richomme, Pascal oth Helesbeux, Jean-Jacques oth Séraphin, Denis oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:202 year:2020 day:15 month:09 pages:0 https://doi.org/10.1016/j.ejmech.2020.112518 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 202 2020 15 0915 0 |
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10.1016/j.ejmech.2020.112518 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001104.pica (DE-627)ELV051059916 (ELSEVIER)S0223-5234(20)30490-6 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Dinh, Chau Phi verfasserin aut Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors 2020transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Vitamin E Elsevier Leukotrienes Elsevier 5-Lipoxygenase Elsevier Inflammation Elsevier Semi-synthesis Elsevier Molecular docking Elsevier Ville, Alexia oth Neukirch, Konstantin oth Viault, Guillaume oth Temml, Veronika oth Koeberle, Andreas oth Werz, Oliver oth Schuster, Daniela oth Stuppner, Hermann oth Richomme, Pascal oth Helesbeux, Jean-Jacques oth Séraphin, Denis oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:202 year:2020 day:15 month:09 pages:0 https://doi.org/10.1016/j.ejmech.2020.112518 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 202 2020 15 0915 0 |
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10.1016/j.ejmech.2020.112518 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001104.pica (DE-627)ELV051059916 (ELSEVIER)S0223-5234(20)30490-6 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Dinh, Chau Phi verfasserin aut Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors 2020transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. Vitamin E Elsevier Leukotrienes Elsevier 5-Lipoxygenase Elsevier Inflammation Elsevier Semi-synthesis Elsevier Molecular docking Elsevier Ville, Alexia oth Neukirch, Konstantin oth Viault, Guillaume oth Temml, Veronika oth Koeberle, Andreas oth Werz, Oliver oth Schuster, Daniela oth Stuppner, Hermann oth Richomme, Pascal oth Helesbeux, Jean-Jacques oth Séraphin, Denis oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:202 year:2020 day:15 month:09 pages:0 https://doi.org/10.1016/j.ejmech.2020.112518 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 202 2020 15 0915 0 |
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Enthalten in Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles Amsterdam [u.a.] volume:202 year:2020 day:15 month:09 pages:0 |
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Dinh, Chau Phi @@aut@@ Ville, Alexia @@oth@@ Neukirch, Konstantin @@oth@@ Viault, Guillaume @@oth@@ Temml, Veronika @@oth@@ Koeberle, Andreas @@oth@@ Werz, Oliver @@oth@@ Schuster, Daniela @@oth@@ Stuppner, Hermann @@oth@@ Richomme, Pascal @@oth@@ Helesbeux, Jean-Jacques @@oth@@ Séraphin, Denis @@oth@@ |
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structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors |
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Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors |
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Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. |
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Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. |
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Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders. Leukotrienes (LT), biosynthesized from arachidonic acid by 5-lipoxygenase (5-LO), constitute a potent family of pro-inflammatory lipid mediators. δ-Garcinoic acid (δ-GA) (1), a natural vitamin E analogue, was chosen for further structural optimization as it selectively inhibited 5-LO activity in cell-free and cell-based assays without impairing the production of specialized pro-resolving mediators by 15-LO. A model of semi-quantitative prediction of 5-LO inhibitory potential developed during the current study allowed the design of 24 garcinamides that were semi-synthesized. In accordance with the prediction model, biological evaluations showed that eight compounds potently inhibited human recombinant 5-LO (IC50 < 100 nM). Interestingly, four compounds were substantially more potent than 1 in activated primary human neutrophils assays. Structure - activity relationships shed light on a supplementary hydrophobic pocket in the allosteric binding site that could be fitted with an aromatic ring. |
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Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors |
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