Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit OfSimplified Structures and Potent β--Acetylhexosaminidase Inhibition

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2020 Mar 29

PMID 32218360

Citations 1

Authors

Xin Yan

Yuna Shimadate

Atsushi Kato

Yi-Xian Li

Yue-Mei Jia

George W J Fleet

Chu-Yi Yu

Affiliations

Soon will be listed here.

Abstract

Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the -acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.

Citing Articles

Multivalent Pyrrolidine Iminosugars: Synthesis and Biological Relevance.

Wang Y, Xiao J, Meng A, Liu C Molecules. 2022; 27(17).

PMID: 36080188 PMC: 9457877. DOI: 10.3390/molecules27175420.

References

Marcelo F, He Y, Yuzwa S, Nieto L, Jimenez-Barbero J, Sollogoub M . Molecular basis for inhibition of GH84 glycoside hydrolases by substituted azepanes: conformational flexibility enables probing of substrate distortion. J Am Chem Soc. 2009; 131(15):5390-2. DOI: 10.1021/ja809776r. View

Tran A, Luo B, Jagadeesh Y, Auberger N, Desire J, Nakagawa S . Synthesis of pyrrolidine-based analogues of 2-acetamidosugars as N-acetyl-D-glucosaminidase inhibitors. Carbohydr Res. 2015; 409:56-62. DOI: 10.1016/j.carres.2015.02.014. View

Li H, Marcelo F, Bello C, Vogel P, Butters T, Rauter A . Design and synthesis of acetamido tri- and tetra-hydroxyazepanes: potent and selective beta-N-acetylhexosaminidase inhibitors. Bioorg Med Chem. 2009; 17(15):5598-604. DOI: 10.1016/j.bmc.2009.06.022. View

Wu Q, Kinami K, Kato A, Li Y, Fleet G, Yu C . Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues. Molecules. 2019; 24(20). PMC: 6832352. DOI: 10.3390/molecules24203712. View

Ayers B, Ngo N, Jenkinson S, Martinez R, Shimada Y, Adachi I . Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone. J Org Chem. 2012; 77(18):7777-92. DOI: 10.1021/jo301243s. View

Ganesan M, Madhukarrao R, Ramesh N . Design and synthesis of new amino-modified iminocyclitols: selective inhibitors of alpha-galactosidase. Org Biomol Chem. 2010; 8(7):1527-30. DOI: 10.1039/b926123k. View

Cheng T, Chan T, Tsou E, Chang S, Yun W, Yang P . From natural product-inspired pyrrolidine scaffolds to the development of new human Golgi α-mannosidase II inhibitors. Chem Asian J. 2013; 8(11):2600-4. DOI: 10.1002/asia.201300680. View

Murahashi S, Imada Y . Synthesis and Transformations of Nitrones for Organic Synthesis. Chem Rev. 2019; 119(7):4684-4716. DOI: 10.1021/acs.chemrev.8b00476. View

Yuzwa S, Macauley M, Heinonen J, Shan X, Dennis R, He Y . A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008; 4(8):483-90. DOI: 10.1038/nchembio.96. View

10.

Li Y, Huang M, Yamashita Y, Kato A, Jia Y, Wang W . L-DMDP, L-homoDMDP and their C-3 fluorinated derivatives: synthesis and glycosidase-inhibition. Org Biomol Chem. 2011; 9(9):3405-14. DOI: 10.1039/c0ob01063d. View

11.

Suzuki K, Nakahara T, Kanie O . 3,4-Dihydroxypyrrolidine as glycosidase inhibitor. Curr Top Med Chem. 2009; 9(1):34-57. DOI: 10.2174/156802609787354315. View

12.

Glawar A, Best D, Ayers B, Miyauchi S, Nakagawa S, Aguilar-Moncayo M . Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: the effect of N-alkylation on hexosaminidase inhibition. Chemistry. 2012; 18(30):9341-59. DOI: 10.1002/chem.201200110. View

13.

Win-Mason A, Jongkees S, Withers S, Tyler P, Timmer M, Stocker B . Stereoselective total synthesis of aminoiminohexitols via carbamate annulation. J Org Chem. 2011; 76(23):9611-21. DOI: 10.1021/jo201151b. View

14.

Takebayashi M, Hiranuma S, Kanie Y, Kajimoto T, Kanie O, Wong C . A Versatile Synthetic Strategy for the Preparation and Discovery of New Iminocyclitols as Inhibitors of Glycosidases. J Org Chem. 2021; 64(14):5280-5291. DOI: 10.1021/jo9902446. View

15.

Umezawa H, Aoyagi T, Komiyama T, Morishima H, Hamada M . Purification and characterization of a sialidase inhibitor, siastatin, produced by Streptomyces. J Antibiot (Tokyo). 1974; 27(12):963-9. DOI: 10.7164/antibiotics.27.963. View

16.

Song Y, Kinami K, Kato A, Jia Y, Li Y, Fleet G . First total synthesis of (+)-broussonetine W: glycosidase inhibition of natural product & analogs. Org Biomol Chem. 2016; 14(22):5157-74. DOI: 10.1039/c6ob00720a. View

17.

Glawar A, Jenkinson S, Thompson A, Nakagawa S, Kato A, Butters T . 3-Hydroxyazetidine carboxylic acids: non-proteinogenic amino acids for medicinal chemists. ChemMedChem. 2013; 8(4):658-66. DOI: 10.1002/cmdc.201200541. View

18.

Kessler M, Acuto O, Storelli C, Murer H, Muller M, Semenza G . A modified procedure for the rapid preparation of efficiently transporting vesicles from small intestinal brush border membranes. Their use in investigating some properties of D-glucose and choline transport systems. Biochim Biophys Acta. 1978; 506(1):136-54. DOI: 10.1016/0005-2736(78)90440-6. View

19.

Cheng W, Wang J, Li H, Lu S, Hu J, Yun W . Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency. Eur J Med Chem. 2016; 123:14-20. DOI: 10.1016/j.ejmech.2016.07.025. View

20.

Glawar A, Martinez R, Ayers B, Hollas M, Ngo N, Nakagawa S . Structural essentials for β-N-acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids. Org Biomol Chem. 2016; 14(44):10371-10385. DOI: 10.1039/c6ob01549b. View