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Takeshi Yamada - One of the best experts on this subject based on the ideXlab platform.
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stereoselective formation of tetrahydrofuran rings via 3 2 annulation total synthesis of plakortone l
Organic Letters, 2014Co-Authors: Hideyuki Sugimura, Shougo Sato, Kensei Tokudome, Takeshi YamadaAbstract:The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective formation of a substituted tetrahydrofuran system, which is converted to a bicyclic Lactone Derivative via consecutive deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton–McCombie deoxygenation. The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.
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Stereoselective Formation of Tetrahydrofuran Rings via [3 + 2] Annulation: Total Synthesis of Plakortone L
Organic Letters, 2014Co-Authors: Hideyuki Sugimura, Shougo Sato, Kensei Tokudome, Takeshi YamadaAbstract:The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective formation of a substituted tetrahydrofuran system, which is converted to a bicyclic Lactone Derivative via consecutive deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton–McCombie deoxygenation. The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.
Hideyuki Sugimura - One of the best experts on this subject based on the ideXlab platform.
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Total Synthesis of (+)-Pyrenolide D
2018Co-Authors: Yuya Ogawa, Marina Kato, Ikuo Sasaki, Hideyuki SugimuraAbstract:An efficient approach to stereoselective construction of a spiro-γ-Lactone core structure via BF3-promoted formal [3 + 2] annulation of aldehydo-aldose Derivatives with γ-methylene-γ-butyroLactone has been developed. The spiro-γ-Lactone Derivative was then used in an efficient total synthesis of (+)-pyrenolide D. The developed chemistry paves the way for total synthesis of structurally diverse natural products containing spiro-Lactone cores
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stereoselective formation of tetrahydrofuran rings via 3 2 annulation total synthesis of plakortone l
Organic Letters, 2014Co-Authors: Hideyuki Sugimura, Shougo Sato, Kensei Tokudome, Takeshi YamadaAbstract:The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective formation of a substituted tetrahydrofuran system, which is converted to a bicyclic Lactone Derivative via consecutive deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton–McCombie deoxygenation. The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.
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Stereoselective Formation of Tetrahydrofuran Rings via [3 + 2] Annulation: Total Synthesis of Plakortone L
Organic Letters, 2014Co-Authors: Hideyuki Sugimura, Shougo Sato, Kensei Tokudome, Takeshi YamadaAbstract:The [3 + 2] annulation of 2,3-O-isopropylidene-aldehydo-aldose with methallyl ether leads to the stereoselective formation of a substituted tetrahydrofuran system, which is converted to a bicyclic Lactone Derivative via consecutive deprotection, oxidative cleavage of the terminal diol, oxidation of the resulting lactol, and Barton–McCombie deoxygenation. The efficiency of this process was demonstrated by the first total synthesis of Plakortone L.
Nuno M. F. S. A. Cerqueira - One of the best experts on this subject based on the ideXlab platform.
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Total Stereoselective Michael Addition of N- and S- Nucleophiles to a d-Erythrosyl 1,5-Lactone Derivative. Experimental and Theoretical Studies Devoted to the Synthesis of 2,6-Dideoxy-4-functionalized-d- ribono-hexono-1,4-Lactone.
The Journal of organic chemistry, 2018Co-Authors: Juliana F. Rocha, David S. Freitas, Jennifer Noro, Carla Silva S. Teixeira, Cristina E. A. Sousa, Maria J. Alves, Nuno M. F. S. A. CerqueiraAbstract:The synthesis of a 1,5-Lactone 2,4- O-alkylidene-d-erythrose Derivative was found to be a highly stereoselective template in Michael addition trough the reaction of a d-erythrosyl 1,5-Lactone Derivative with nitrogen and sulfur nucleophiles. The sulfur adducts formed are 1 (d-erythrose Derivative):1 (nucleophile), and the nitrogen adducts are 1:2. Both were then treated under HCl to give 2,6-dideoxy-4-functionalized-d- ribono-hexono-1,4-Lactone by a reaction cascade in high overall yield. Reaction's scale up even improves the yield. The theoretical and computational results clearly explain the origin of the stereoselectivity, and the energetic course of reactions starting with nitrogen and sulfide nucleophiles. Considering that the 1,4-Lactones obtained in this work offer a new molecular scaffold for organic synthesis, these new results provide a solid theoretical platform that can be used to speed up synthesis of other Derivatives in a stereo- and regioselective way.
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Total Stereoselective Michael Addition of N- and S- Nucleophiles to a d‑Erythrosyl 1,5-Lactone Derivative. Experimental and Theoretical Studies Devoted to the Synthesis of 2,6-Dideoxy-4-functionalized‑d-ribono-hexono-1,4-Lactone
2018Co-Authors: Juliana F. Rocha, David S. Freitas, Jennifer Noro, Carla Silva S. Teixeira, Cristina E. A. Sousa, Maria J. Alves, Nuno M. F. S. A. CerqueiraAbstract:The synthesis of a 1,5-Lactone 2,4-O-alkylidene-d-erythrose Derivative was found to be a highly stereoselective template in Michael addition trough the reaction of a d-erythrosyl 1,5-Lactone Derivative with nitrogen and sulfur nucleophiles. The sulfur adducts formed are 1 (d-erythrose Derivative):1 (nucleophile), and the nitrogen adducts are 1:2. Both were then treated under HCl to give 2,6-dideoxy-4-functionalized-d-ribono-hexono-1,4-Lactone by a reaction cascade in high overall yield. Reaction’s scale up even improves the yield. The theoretical and computational results clearly explain the origin of the stereoselectivity, and the energetic course of reactions starting with nitrogen and sulfide nucleophiles. Considering that the 1,4-Lactones obtained in this work offer a new molecular scaffold for organic synthesis, these new results provide a solid theoretical platform that can be used to speed up synthesis of other Derivatives in a stereo- and regioselective way
Lie-fen Shyur - One of the best experts on this subject based on the ideXlab platform.
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phytoagent deoxyelephantopin and its Derivative inhibit triple negative breast cancer cell activity through ros mediated exosomal activity and protein functions
Frontiers in Pharmacology, 2017Co-Authors: Kuo Hsiung Lee, Kyoko Nakagawagoto, Jeng Yuan Shiau, Yong Qun Chang, Lie-fen ShyurAbstract:A novel plant sesquiterpene Lactone Derivative, DET Derivative (DETD)-35, originating from parental deoxyelephantopin (DET) was previously observed to effectively suppress human triple negative breast cancer (TNBC) MDA-MB-231 cell activity and tumor growth in mice. In this study, the mechanisms underlying the activity of DETD-35 were elucidated. DET and DETD-35 induced reactive oxygen species (ROS) which caused structural damage and dysfunction of mitochondria and increased cytosolic calcium level, subsequently evoking exosome release from the cancer cells. Intriguingly, exosomes induced by both compounds had an atypical function. Cancer cell-derived exosomes commonly show metastatic potential, but upon DET/DETD-35 treatment exosomes showed anti-proliferative activity against MDA-MB-231 cells. Quantitative proteome analysis of TNBC cell-secreted exosomes showed that DET and DETD-35 attenuated the expression of proteins related to cell migration, cell adhesion, and angiogenesis. Furthermore, several exosomal proteins participating in biological mechanisms such as oxidative stress and decrease of transmembrane potential of mitochondria were found deregulated by treatment with either compound. Pretreatment with ROS scavenger, N-acetylcysteine, blockaded DET- or DETD-35-induced oxidative stress and calcium dependent exosome release mechanisms, and also reverted DET- or DETD-35-induced reprogramming exosomal protein expression profiles resulting in attenuation of exosomal toxicity against TNBC cell proliferation. In summary, this study shows that a plant-derived sesquiterpene Lactone DET and its analog DETD-35 inhibitory TNBC cell activities through oxidative stress-induced cancer cell releasing exosomes in tandem with alteration of exosomal protein composition and functions. The findings of this study suggest that DETD-35 may be suitable for further development into an anti-TNBC drug.
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a novel plant sesquiterpene Lactone Derivative detd 35 suppresses brafv600e mutant melanoma growth and overcomes acquired vemurafenib resistance in mice
Molecular Cancer Therapeutics, 2016Co-Authors: Jia-hua Feng, Kuo Hsiung Lee, Lie-fen Shyur, Kyoko NakagawagotoAbstract:Acquired resistance to vemurafenib develops through reactivation of RAF/MEK/ERK signaling or bypass mechanisms. Recent combination therapies such as a MEK inhibitor combined with vemurafenib show improvement in major clinical end points, but the percentage of patients with adverse toxic events is higher than with vemurafenib monotherapy and most patients ultimately relapse. Therefore, there is an urgent need to develop new antimelanoma drugs and/or adjuvant agents for vemurafenib therapy. In this study, we created a novel semiorganically modified Derivative, DETD-35, from deoxyelephantopin (DET), a plant sesquiterpene Lactone demonstrated as an anti-inflammatory and anti-mammary tumor agent. Our results show that DETD-35 inhibited proliferation of a panel of melanoma cell lines, including acquired vemurafenib resistance A375 cells (A375-R) established in this study, with superior activities to DET and no cytotoxicity to normal melanocytes. DETD-35 suppressed tumor growth and reduced tumor mass as effectively as vemurafenib in A375 xenograft study. Furthermore, DETD-35 also reduced tumor growth in both acquired (A375-R) and intrinsic (A2058) vemurafenib resistance xenograft models, where vemurafenib showed no antitumor activity. Notably, the combination of DETD-35 and vemurafenib exhibited the most significant effects in both in vitro and in vivo xenograft studies due to synergism of the compound and the drug. Mechanistic studies suggested that DETD-35 overcame acquired vemurafenib resistance at least in part through deregulating MEK-ERK, Akt, and STAT3 signaling pathways and promoting apoptosis of cancer cells. Overall, our results suggest that DETD-35 may be useful as a therapeutic or adjuvant agent against BRAF(V600E) mutant and acquired vemurafenib resistance melanoma. Mol Cancer Ther; 15(6); 1163-76. ©2016 AACR.
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Abstract B175: A novel plant sesquiterpene Lactone Derivative DETD suppresses BRAFV600E mutant melanoma growth and overcomes acquired vemurafenib resistance in mice
Therapeutic Agents: Other, 2015Co-Authors: Jia-hua Feng, Kyoko Nakagawa-goto, Kuo Hsiung Lee, Lie-fen ShyurAbstract:Melanoma is the most lethal form of skin cancer and cases are increasing year by year. BRAFV600E mutation is found approximately in 50% of melanoma patients that drives MAPK (RAF/MEK/ERK) signaling for cancer progression. Vemurafenib, a small molecule that specifically targets BRAFV600E mutation, received FDA approval for treatment of late-stage melanoma in 2011. Unfortunately, patients develop acquired vemurafenib resistance via reactivation of MAPK signaling or bypass mechanisms. Recent combination therapy such as MEK inhibitor combined with vemurafenib shows improvement in major clinical end points but percentage of patients with adverse toxic events are higher compared to vemurafenib monotherapy and most patients relapse ultimately. It is therefore an urgent need to develop new anti-melanoma drug and/or adjuvant agent for vemurafenib therapy. In this study, we created a novel semi-organically modified Derivative DETD from deoxyelephantopin (DET), a plant sesquiterpene Lactone demonstrated as an anti-inflammatory and anti-mammary tumor agent in our laboratory. DETD suppressed both parental human BRAFV600E mutant melanoma (A375) and vemurafenib resistance melanoma (A375-R) cell proliferation in vitro. Furthermore, through compound drug combination assay, DETD and vemurafenib was found to show synergism in suppressing proliferation, conoly formation and inducing apoptosis of A375 melanoma cell. In A375 xenograft study, DETD suppressed tumor growth and reduced tumor mass by 70.5%, as effective as vemurafenib (71.9%), compared to tumor control group. Moreover, compound-drug combinational treatment with alternate administration of DETD and vemurafenib also showed similar tumor growth inhibition efficacy by 72.3%, suggesting in vivo synergistic or additive effect of DETD and vemurafenib. In A375-R xenograft study, vemurafenib treatment showed little or no anti-tumor activity with similar tumor growth rate and sizes relative to the tumor control group, whereas DETD could reduce A375-R tumor growth and mass with 46.9%. Notably, the combination of DETD and vemurafenib treatment exhibited the most significant effect, with a 65.3% reduction in tumor mass. Our mechanistic studies revealed the activation of non-receptor tyrosine kinase Src and its downstream signaling pathways, including MAPK, Akt and STAT3 pathways in the vemurafenib resistant melanoma A375-R, and DETD could de-regulate the activation of all these multi- kinase signaling pathways. Overall, our results offer strong evidence of DETD in inhibiting BRAFV600E melanoma growth and its acquired vemurafenib resistance in mice that suggest DETD might have great therapeutic or adjuvant potential in management of melanoma patients with BRAFV600E mutation. Citation Format: Jia-Hua Feng, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, Lie-Fen Shyur. A novel plant sesquiterpene Lactone Derivative DETD suppresses BRAFV600E mutant melanoma growth and overcomes acquired vemurafenib resistance in mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B175.
Carola Gallo-rodriguez - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of trisaccharides containing internal galactofuranose O-linked in Trypanosoma cruzi mucins
Carbohydrate research, 2009Co-Authors: Verónica M. Mendoza, Rosa M De Lederkremer, Gustavo A. Kashiwagi, Carola Gallo-rodriguezAbstract:Abstract The trisaccharides β- d -Gal f -(1→2)-β- d -Gal f -(1→4)- d -GlcNAc ( 5 ) and β- d -Gal p -(1→2)-β- d -Gal f -(1→4)- d -GlcNAc ( 6 ) constitute novel structures isolated as alditols when released by reductive β-elimination from mucins of Trypanosoma cruzi (Tulahuen strain). Trisaccharides 5 and 6 were synthesized employing the aldonoLactone approach. Thus, a convenient d -galactono-1,4-Lactone Derivative was used for the introduction of the internal galactofuranose and the trichloroacetimidate method was employed for glycosylation reactions. Due to the lack of anchimeric assistance on O-2 of the galactofuranosyl precursor, glycosylation studies were performed under different conditions. The nature of the solvent strongly determined the stereochemical course of the glycosylation reactions when the galactofuranosyl donor was substituted either by 2- O -Gal p or 2- O -Gal f .
