Article
Chemistry, Medicinal
Yoshihide Usami, Yoshino Mizobuchi, Mai Ijuin, Takeshi Yamada, Mizuki Morita, Koji Mizuki, Hiroki Yoneyama, Shinya Harusawa
Summary: The enantiomers of 6-halo-substituted pericosine A derivatives, including pericoxide, were synthesized. These derivatives showed moderate antitumor activity against three types of tumor cell lines, with the bromo- and iodo-congeners having similar activity to pericosine A. The fluorinated compound was less active. There was no significant difference in potency between the enantiomers of the halogenated compounds in the antitumor assay.
Article
Chemistry, Organic
Sara Mazeh, M. Dolores Garcia-Fernandez, Barbara Pelletier, Christophe Moreau, Philippe Delair
Summary: This paper presents a novel approach for synthesizing the (-)-205B alkaloid. The method utilizes an intramolecular alkylation reaction with a silyl tether to achieve efficient chirality transfer, an unprecedented tandem highly selective iridium catalyzed partial reduction of lactam coupled with an acid promoted aza-Prins reaction, and an almost complete stereochemical control in Shenvi's radical hydrogen atom transfer on an exocyclic methylene. The second part of the research demonstrates the positive allosteric behavior of this natural alkaloid towards alpha 7 nAChRs, in contrast to the inhibitory effect of the unnatural enantiomer.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
Yi-Xian Li, Jun-Zhe Wang, Yuna Shimadate, Maki Kise, Atsushi Kato, Yue-Mei Jia, George W. J. Fleet, Chu-Yi Yu
Summary: The C-7 fluorinated derivatives of casuarine and australine, important polyhydroxylated pyrrolizidines, were successfully synthesized using organocatalytic stereoselective alpha-fluorination of aldehydes as a key step. This strategy can also be applied to the synthesis of challenging fluorinated iminosugars and carbohydrates. Docking studies revealed that the potent inhibitions of trehalase and amyloglucosidase by the fluorinated polyhydroxylated pyrrolizidines are mainly due to the interaction of fluorine atoms in these iminosugars with the amino acid residues of the corresponding enzymes. Additionally, unusual anion-pi interactions were established between the C-7 fluoride and a hydrophobic pocket in amyloglucosidase. These unexpected docking modes and structure-activity relationship studies highlight the significance of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Jerome Desire, Quentin Foucart, Ana Poveda, Gurvan Gourlaouen, Yuna Shimadate, Maki Kise, Cameron Proceviat, Roger Ashmus, David J. Vocadlo, Jesus Jimenez-Barbero, Atsushi Kato, Yves Bleriot
Summary: A series of bicyclic iminosugar C-glycosides based on an octahydrofuro[3,2-b]pyridine motif have been synthesized. These carbohydrate mimics showed promising inhibitory activity against glycosidases, suggesting their potential for drug development.
CARBOHYDRATE RESEARCH
(2022)
Article
Chemistry, Medicinal
Tian-Tian Lu, Yuna Shimadate, Bin Cheng, Uta Kanekiyo, Atsushi Kato, Jun-Zhe Wang, Yi-Xian Li, Yue-Mei Jia, George W. J. Fleet, Chu-Yi Yu
Summary: 5-C-Alkyl-DNJ and 5-C-alkyl-L-ido-DNJ derivatives were efficiently synthesized from a t-sorbose-derived cyclic nitrone and tested for their inhibitory effects on glycosidases. Results showed that the length of the C-5 alkyl chain influenced enzyme inhibition, which could be important for designing alpha-glucosidase inhibitors for the treatment of viral infections and type II diabetes.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Brendan J. Byatt, Atsushi Kato, Stephen G. Pyne
Summary: The iminosugar core of natural glyphaeaside C, originally thought to be a derivative of DNJ, has been revised as a derivative of L-DMDP through the total synthesis of its enantiomer. This novel L-DMDP-derived configuration is the first of its kind observed in nature, and the prepared iminosugars showed nanomolar inhibition of bovine liver beta-glucosidase and beta-galactosidase.
Article
Chemistry, Organic
Lucas Dada, Juan Pablo Colomer, Veronica E. Manzano, Oscar Varela
Summary: A series of benzyl beta-d-Gal-S-(1 -> 4)-3-deoxy-4-thio-alpha-d-hexopyranosides were synthesized for the search of new glycosidase inhibitors. Different configurations and substitutions were tested, and it was found that benzyl thiodisaccharides were better inhibitors than substituted ones. The inhibitory activity of thiodisaccharides with a hexopyranoside moiety was weaker, except for those with alpha-d-xylo configuration. The interaction between the enzyme and inhibitor was affected by the configuration and substitution pattern of the 3-deoxy-4-thiopyranoside.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
Alexander Garay-Talero, Tales A. C. Goulart, Rafael D. C. Gallo, Roberto do C. Pinheiro, Catalina Hoyos-Orozco, Igor D. Jurberg, Diego Gamba-Sanchez
Summary: An aza-Robinson annulation strategy involving NaOEt-catalyzed conjugate addition of cyclic imides onto vinyl ketones and TfOH-mediated intramolecular aldol condensation has been developed for the synthesis of densely functionalized fused bicyclic amides. The potential use of these amides in the synthesis of alkaloids has been demonstrated by the conversion of appropriate precursors to (+/-)-coniceine and quinolizidine in two additional steps, achieving overall yields of 40% and 44%, respectively.
Article
Chemistry, Multidisciplinary
Li-Xuan Li, Long Min, Tian-Bing Yao, Shu-Xiao Ji, Chuang Qiao, Pei-Lin Tian, Jianwei Sun, Chuang-Chuang Li
Summary: The first total synthesis of daphgraciline, a member of Daphniphyllum yuzurine-type alkaloids, has been achieved. The unique structure of the yuzurine-type subfamily was efficiently assembled using a novel method, and the complex skeleton and key moiety were successfully constructed. This study provides a foundation for the further synthesis of enantioenriched daphgraciline with high stereochemistry.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Multidisciplinary Sciences
Stone Woo, Ryan A. Shenvi
Summary: The ingestion of alkaloid metabolites from the bark of Galbulimima tree can lead to psychotropic and excitatory effects in humans. However, the limited supply of these alkaloids has hindered their exploration and development. In this study, researchers report a solution to the supply problem of GB18, a unique compound found in Galbulimima bark that is believed to have psychotropic effects. By developing new chemical reactions, the researchers were able to synthesize a large amount of GB18 and found it to be a potent antagonist of kappa- and mu-opioid receptors. This discovery opens up new possibilities for understanding the biological activity of Galbulimima metabolites.
Article
Chemistry, Organic
Hongbin Zhai, Zhenhua Wang, Kewei Chen, Tian-Yu Sun, Jian Wei, Yun-Dong Wu
Summary: The first asymmetric total synthesis of indole alkaloid arbophyllidine has been achieved, featuring key reactions such as intramolecular reductive Heck reaction, Fischer indolization, and oxidative lactonization. Density functional theory calculations were employed to provide a comprehensive understanding of the oxidative lactonization.
ORGANIC CHEMISTRY FRONTIERS
(2022)
Article
Biochemistry & Molecular Biology
David M. Campkin, Yuna Shimadate, Barbara Bartholomew, Paul Bernhardt, Robert J. Nash, Jennette A. Sakoff, Atsushi Kato, Michela Simone
Summary: Novel tetrachlorinated phthalimide analogues with boron-pinacolate ester group were synthesized and evaluated for their potential applications in glycosidase modulation and cancer treatment, showing promising potency and selectivity for certain molecules.
Article
Chemistry, Medicinal
Jun-Zhe Wang, Bin Cheng, Atsushi Kato, Maki Kise, Yuna Shimadate, Yue-Mei Jia, Yi-Xian Li, George W. J. Fleet, Chu-Yi Yu
Summary: This study designed and synthesized two series of C-4 alkylated and arylated LAB and DAB derivatives, and evaluated their activity against various glycosidases. The results revealed potential inhibitory effects of some derivatives and provided guidance for drug design and development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Tae Hyun Kim, Jong Hyeok Park, Jooyeon Park, Dong Min Son, Ji-Young Baek, Hee Jun Jang, Won Ki Jung, Youngjoo Byun, Sang Kyum Kim, Song-Kyu Park
Summary: (R)-crizotinib can induce changes in cancer cells and cancer stem cells properties by inhibiting AMPK, resulting in alterations in cellular morphology and characteristics.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Serdar Burmaoglu, Ali Osman Yilmaz, M. Fatih Polat, Ruya Kaya, Ilhami Gulcin, Oztekin Algul
Summary: In this study, novel tris-chalcones were synthesized and tested for their inhibitory effects on human enzymes, showing promising potential for the treatment of glaucoma, leukemia, epilepsy, and Alzheimer's disease.
ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Jerome Desire, Quentin Foucart, Ana Poveda, Gurvan Gourlaouen, Yuna Shimadate, Maki Kise, Cameron Proceviat, Roger Ashmus, David J. Vocadlo, Jesus Jimenez-Barbero, Atsushi Kato, Yves Bleriot
Summary: A series of bicyclic iminosugar C-glycosides based on an octahydrofuro[3,2-b]pyridine motif have been synthesized. These carbohydrate mimics showed promising inhibitory activity against glycosidases, suggesting their potential for drug development.
CARBOHYDRATE RESEARCH
(2022)
Article
Chemistry, Medicinal
Atsushi Kato, Izumi Nakagome, Uta Kanekiyo, Tian-Tian Lu, Yi-Xian Li, Kosuke Yoshimura, Mana Kishida, Kenta Shinzawa, Tomoki Yoshida, Nobutada Tanaka, Yue-Mei Jia, Robert J. Nash, George W. J. Fleet, Chu-Yi Yu
Summary: In recent years, pharmacological chaperones have been recognized as thermodynamic stabilizers in combination therapy. This study focused on designing a high-affinity ligand for lysosomal acid alpha-glucosidase (GAA) using alkyl branches on 1-deoxynojirimycin (DNJ). The results showed that 5-C-heptyl-DNJ significantly improved the stability of recombinant human acid alpha-glucosidase (rhGAA) and increased intracellular GAA activities in cells from Pompe disease patients.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Organic
Ming Zhang, Hong-Wei Chen, Qing-Quan Liu, Feng-Teng Gao, Yi-Xian Li, Xiang-Guo Hu, Chu-Yi Yu
Summary: This article presents a new method for synthesizing rare sugars, and demonstrates its utility by synthesizing fluorinated analogues of sugars.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
J. Bouquet, N. Auberger, R. Ashmus, D. King, A. Bordes, N. Fontelle, S. Nakagawa, Z. Madden, C. Proceviat, A. Kato, J. Desire, D. J. Vocadlo, Y. Bleriot
Summary: The synthesis and evaluation of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold as inhibitors of functionally related exo-N-acetylhexosaminidases were reported. The study explored the effects of epimerization and C-alkylation at specific positions, leading to the identification of selective inhibitors for different hexosaminidases.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Olumayokun A. Olajide, Victoria U. Iwuanyanwu, Owolabi W. Banjo, Atsushi Kato, Yana B. Penkova, George W. J. Fleet, Robert J. Nash
Summary: This study found that idoBR1, a cucumber-derived iminosugar amino acid, could dose-dependently reduce the inflammatory responses in LPS-activated microglia cells. These findings suggest that idoBR1 may have anti-inflammatory effects and could be further investigated for its potential in other neurodegenerative diseases.
Article
Chemistry, Medicinal
Dong Zi, Ying-Ying Song, Tian-Tian Lu, Maki Kise, Atsushi Kato, Jun-Zhe Wang, Yue-Mei Jia, Yi-Xian Li, George W. J. Fleet, Chu-Yi Yu
Summary: A series of alpha-1-C-alkyl DAB and LAB derivatives have been designed as analogues of broussonetine W and assayed as glycosidase inhibitors. Introducing substituents on the terminal aryl or hydroxyl groups decreased their alpha-glucosidase inhibitions but improved their inhibitions of bovine liver beta-glucosidase and beta-galactosidase. The compounds also showed potent inhibitions of human lysosome beta-glucosidase and docking calculations revealed novel binding modes.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Kai-Cheng Yu, Hai Li, Yuan-Hong Tu, Hui Zhao, Xiang-Guo Hu
Summary: We have developed a non-toxic and non-corrosive dual copper/photoredox-catalyzed method for the synthesis of P(O)-N bond from commercially available compounds. This method has a broad substrate scope and is suitable for the direct modification of drug molecules.
Article
Chemistry, Medicinal
Atsushi Kato, Izumi Nakagome, Maki Kise, Kousuke Yoshimura, Nobutada Tanaka, Robert J. Nash, George W. J. Fleet, Yota Kobayashi, Hayato Ikeda, Takuya Okada, Naoki Toyooka
Summary: This study presents a strategy for designing a practical ligand for lysosomal acid alpha-glucosidase (GAA) with a focus on N-alkyl derivatives of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). The optimized N-4'-(p-trifluoromethylphenyl)butyl-DAB (5g) showed significantly higher affinity for GAA compared to N-butyl-DAB (3f). Docking analysis revealed the accommodation of the phenyl group of 5g in a lipophilic pocket and the stabilizing effect of the p-trifluoromethyl group.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Plant Sciences
Brendan J. Byatt, Atsushi Kato, Stephen G. Pyne
Summary: The 10 glyphaeaside alkaloids isolated from the roots of Glyphaea brevis were originally believed to be piperidine-based 1-C-alkylated iminosugars with different ring configurations. However, further studies showed that glyphaeaside C is a pyrrolidine-based iminosugar with a revised ring configuration. Synthesis experiments were conducted to confirm the structure of glyphaeaside C and related derivatives. The inhibitory activity of these compounds against glycosidases was also examined, revealing their potential as inhibitors.
JOURNAL OF NATURAL PRODUCTS
(2023)
Article
Biochemistry & Molecular Biology
Jerome Desire, Zakaria Debbah, David Gueyrard, Jerome Marrot, Yves Bleriot, Atsushi Kato
Summary: A series of L-iminosugar C,C-glycosides containing an allyl group and various substituents at the pseudoanomeric position were synthesized and evaluated for their glycosidase inhibition activity. The compounds adopted a 1C4 conformation and showed weaker glycosidase inhibition compared to previously reported branched L-iminosugars. However, some compounds exhibited micromolar inhibition of human lysosome β-glucocerebrosidase, indicating their potential as potent CGase inhibitors by modifying the structure/length of the pseudoanomeric substituents.
CARBOHYDRATE RESEARCH
(2023)
Article
Multidisciplinary Sciences
Huawen Peng, Kaicheng Yu, Xufei Liu, Jiapeng Li, Xiangguo Hu, Qiang Zhao
Summary: Researchers solved the problems of susceptibility to chlorine degradation and low permeance in current polyamide lithium extraction nanofiltration membranes by designing a new quaternized-spiro piperazine monomer and translating its beneficial properties into large-area membranes. The new membranes have high permeance and chlorine resistance, and their performance is stable even after 400 hours of immersion in sodium hypochlorite. The high performance is attributed to the spiral conformation and secondary amine structures of the monomer.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Organic
Dong Zi, Yuna Shimadate, Jun-Zhe Wang, Atsushi Kato, Yi-Xian Li, Yue-Mei Jia, George W. J. Fleet, Chu-Yi Yu
Summary: A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from d-tartrate-derived nitrone 18. Four of the DAB peptides were found to be weak and selective bovine liver beta-galactosidase inhibitors, with the compound 23b showing the most potent beta-galactosidase inhibition. Molecular docking studies revealed different docking modes of compound 23b compared to other DAB peptides, and partial similarity of compound 23b to DGJ.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Organic
Atsushi Kato, Izumi Nakagome, Kosuke Yoshimura, Uta Kanekiyo, Mana Kishida, Kenta Shinzawa, Tian-Tian Lu, Yi-Xian Li, Robert J. Nash, George W. J. Fleet, Nobutada Tanaka, Chu-Yi Yu
Summary: This study demonstrates a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and l-sugar-type iminosugars to change the orientation of binding. The designed ligand, 5-C-methyl-l-ido-DNJ, showed strong affinity for GAA and enhanced enzyme activity and transport in Pompe patient cells.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Hai Li, Kai-Cheng Yu, Jia-Kun Su, Wei Ouyang, Nai-Li Fan, Xiang-Guo Hu
Summary: We have developed a photo-mediated method for the synthesis of C2-phosphinylated carbohydrates from glycals and diarylphosphine oxides. This method avoids the use of over-stoichiometric transition-metal promoters and shows a broader range of substrate compatibility, including substrates with one or even three hydroxy groups. It can also be used for the late-stage modification of complex molecules and the introduction of the phosphorous group to the 6-position of carbohydrates.
Article
Chemistry, Organic
Qiang Pan, Qi-Min Zhou, Pei-Xin Rui, Xiang-Guo Hu
Summary: We have developed an improved cyanide-free strategy for synthesizing glycosyl carboxylic acids through stereoselective C-vinyl glycosylation and oxidative cleavage. This approach reduces the amount of NaIO4 required for oxidative cleavage and expands the substrate scope, leading to the synthesis of undocumented glycosyl carboxylic acids. Furthermore, we demonstrate that protecting groups affect the reaction efficiency in radical C-glycosylation, providing access to stereoselective glycosyl acids.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
