Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Dec 16;58(51):18577-18583.
doi: 10.1002/anie.201908805. Epub 2019 Nov 6.

Expedient Synthesis of Core Disaccharide Building Blocks from Natural Polysaccharides for Heparan Sulfate Oligosaccharide Assembly

Nitin J Pawar  1 , Lei Wang  1 , Takuya Higo  1 , Chandrabali Bhattacharya  1 , Pavan K Kancharla  1 , Fuming Zhang  2 , Kedar Baryal  3 , Chang-Xin Huo  3 , Jian Liu  4 , Robert J Linhardt  2 , Xuefei Huang  3 , Linda C Hsieh-Wilson  1
Affiliations
Review

Expedient Synthesis of Core Disaccharide Building Blocks from Natural Polysaccharides for Heparan Sulfate Oligosaccharide Assembly

Nitin J Pawar et al. Angew Chem Int Ed Engl. .

Abstract

The complex sulfation motifs of heparan sulfate glycosaminoglycans (HS GAGs) play critical roles in many important biological processes. However, an understanding of their specific functions has been hampered by an inability to synthesize large numbers of diverse, yet defined, HS structures. Herein, we describe a new approach to access the four core disaccharides required for HS/heparin oligosaccharide assembly from natural polysaccharides. The use of disaccharides rather than monosaccharides as minimal precursors greatly accelerates the synthesis of HS GAGs, providing key disaccharide and tetrasaccharide intermediates in about half the number of steps compared to traditional strategies. Rapid access to such versatile intermediates will enable the generation of comprehensive libraries of sulfated oligosaccharides for unlocking the "sulfation code" and understanding the roles of specific GAG structures in physiology and disease.

Keywords: carbohydrates; glycosaminoglycans; heparan sulfate; oligosaccharides; synthesis design.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Representative structure found in HS/heparin and core disaccharide building blocks.
Scheme 1.
Scheme 1.
Synthesis of GlcN-IdoA and GlcA-GlcN Building Blocks from Natural Polysaccharides. TfOH = trifluoromethanesulfonic acid, Ac = acetyl, TfN3 = trifluoromethanesulfonyl azide, CbzCl = benzyl chloroformate.
Scheme 2.
Scheme 2.
Epimerization to Form All Four HS Core Disaccharides. NBS = N-bromosuccinimide, AIBN = 2,2′-Azobis(2-methylpropionitrile).
Scheme 3.
Scheme 3.
Differential protection of the GlcN-IdoA building block. TMSSPh = trimethyl(phenylthio)silane, SPh = benzenethiol, DCM = dichloromethane, NapCH(OMe)2 = 2-naphthaldehyde dimethyl acetal, Naph = 2-naphthyl, p-TsOH = p-toluenesulfonic acid, TBAI = tetrabutylammonium iodide, BzCl = benzoyl chloride, MS = molecular sieves, BnBr = benzyl bromide, DMF = dimethylformamide, LevOH = levulinic acid, EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMAP = 4-(dimethylamino)pyridine, TBDPSCl = tert-butyl(chloro)diphenylsilane, Im = imidazole, Py = pyridine, TFAA = trifluoroacetic anhydride, NIS = N-iodosuccinimide. FmocCl = 9-fluorenylmethoxycarbonyl chloride, TFA = trifluoroacetic acid, TFAHN = trifluoroacetamide, STol = 4-methylbenzenethiol, All = allyl.
Scheme 4.
Scheme 4.. A universal tetrasaccharide building block for the generation of diverse HS sequences.
a) Assembly of the strategically protected tetrasaccharide 21. b) Demonstration of the orthogonality of the TBDPS, Nap, Lev, Fmoc, and t-Bu protecting groups. DDQ = 2,3-dichloro-5,6-dicyano-p-benzoquinone.
Scheme 5.
Scheme 5.
Regioselective sulfation of the 2-O, 6-O and N positions to give tetrasaccharides bearing asymmetrical, regiodefined sulfation patterns.
See this image and copyright information in PMC

References

    1. Petitou M, van Boeckel CAA, Angew. Chem. Int. Ed 2004, 43, 3118–3133. - PubMed
    2. Liu J, Thorp SC, Med. Res. Rev 2002, 22, 1–25. - PubMed
    3. Corti F, Wang Y, Rhodes JM, Atri D, Archer-Hartmann S, Zhang J, Zhuang ZW, Chen D, Wang T, Wang Z, Azadi P, Simons M, Nat. Commun 2019, 10 (1), 1562. - PMC - PubMed
    4. Zong C, Venot A, Li X, Lu W, Xiao W, Wilkes J-SL, Salanga CL, Handel TM, Wang L, Wolfert MA, Boons G-J, J. Am. Chem. Soc 2017, 139 (28), 9534–9543. - PMC - PubMed
    5. Vlodavsky I, Gross-Cohen M, Weissmann M, Ilan N, Sanderson RD, Trends. Biochem. Sci 2018, 43 (1), 18–31. - PMC - PubMed
    6. Kaltenbach DD, Jaishankar D, Hao M, Beer JC, Volin MV, Desai UR, Tiwari V, Front Pharmacol. 2018, 9, 1315. - PMC - PubMed
    7. Lortat-Jacob H, Curr. Opin. Struct. Biol 2009, 19 (5), 543–548. - PubMed
    8. Collins LE, Troeberg L, J. Leukoc. Biol 2019, 105 (1), 81–92. - PubMed
    9. Zhang P, Lu H, Peixoto RT, Pines MK, Ge Y, Oku S, Siddiqui TJ, Xie Y, Wu W, Archer-Hartmann S, Yoshida K, Tanaka KF, Aricescu AR, Azadi P, Gordon MD, Sabatini BL, Wong ROL, Craig AM, Cell, 2018, 174 (6), 1450–1464. - PMC - PubMed
    1. Xu D, Esko JD, Annu. Rev. Biochem 2014, 83, 129–157. - PMC - PubMed
    2. Gama CI, Hsieh-Wilson LC, Curr. Opin. Chem. Biol 2005, 9, 609–619. - PubMed
    3. Capila I, Linhardt RJ, Angew. Chem. Int. Ed 2002, 41, 390–412. - PubMed
    1. Shi X, Zaia J, J. Biol. Chem 2009, 284, 11806–11814. - PMC - PubMed
    2. Feyzi E, Saldeen T, Larsson E, Lindahl U, Salmivirta M, J. Biol. Chem 1998, 273, 13395–13398. - PubMed
    3. Brickman YG, Ford MD, Gallagher JT, Nurcombe V, Bartlett PF, Turnbull JE, J. Biol. Chem 1998, 273, 4350–4359. - PubMed
    4. Lindahl U, Kjellén L, J. Intern. Med 2013, 273, 555–571. - PubMed
    5. Nadanaka S,Kitagawa H, J. Biochem 2008, 144, 7–14. - PubMed
    1. Dey S, Wong C-H, Chem. Sci 2018, 9, 6685–6691. - PMC - PubMed
    2. Hu Y-P, Lin S-Y, Huang C-Y, Zulueta MML, Liu J-Y, Chang W, Hung S-C, Nat. Chem 2011, 3, 557–563. - PubMed
    3. Orgueira HA, Bartolozzi A, Schell P; Litjens REJN, Palmacci ER, Seeberger PH, Chem. Eur. J 2003, 9, 140–169. - PubMed
    4. Yang B, Yoshida K, Yin Z, Dai H, Kavunja H, El-Dakdouki MH, Sungsuwan S, Dulaney SB, Huang X, Angew. Chem. Int. Ed 2012, 51, 10185–10189. - PMC - PubMed
    5. Zong C, Huang R, Condac E, Chiu Y, Xiao W, Li X, Lu W, Ishihara M, Wang S, Ramiah A, Stickney M, Azadi P, Amster J, Moremen KW, Wang L, Sharp JS, Boons G-J, J. Am. Chem. Soc 2016, 138, 13059–13067. - PMC - PubMed
    6. Codée JDC, Stubba B, Schiattarella M, Overkleeft HS, van Boeckel CAA, van Boom JH, van der Marel GA, J. Am. Chem. Soc 2005, 127, 3767–3773. - PubMed
    7. Hansen SU, Miller GJ, Cole C, Rushton G, Avizienyte E, Jayson GC; Gardiner JM, Nat. Commun 2013, 4, 2016. - PMC - PubMed
    8. Ojeda R, de Paz J-L, Martín-Lomas M, Chem. Commun 2003, 19, 2486–2487. - PubMed
    9. Xu Y, Masuko S, Takieddin M, Xu H, Liu R, Jing J, Mousa SA, Linhardt RJ,; J. Liu, Science, 2011, 334, 498–501. - PMC - PubMed
    10. Chen Y, Li Y, Yu H, Sugiarto G, Thon V, Hwang J, Ding L, Hie L, Chen X, Angew. Chem. Int. Ed 2013, 52, 11852–11856. - PMC - PubMed
    11. Wu B, Wei N, Thon V, Wei M, Yu Z, Xu Y, Chen X, Liu J, Wang PG, Li T, Org. Biomol. Chem 2015, 13, 5098–5101. - PMC - PubMed
    12. Mende M, Bednarek C, Wawryszyn M, Sauter P, Biskup MB, Schepers U, Bräse S, Chem. Rev 2016, 116, 8193–8255. - PubMed
    13. Hansen SU, Baráth M, Salameh BAB, Pritchard RG, Stimpson WT, Gardiner JM, Jayson GC, Org. Lett 2009, 11, 4528–4531. - PubMed
    14. Hansen SU, Dalton CE, Baráth M, Kwan G, Raftery J, Jayson GC, Miller GJ, Gardiner JM, J. Org. Chem 2015, 80, 3777–3789. - PubMed
    15. Hu Y-P, Zhong Y-Q, Chen Z-G, Chen C-Y, Shi Z, Zulueta MML, Ku C-C, Lee P-Y, Wang C-C, Hung S-C, J. Am. Chem. Soc 2012, 134, 20722–20727. - PubMed
    1. Liu X, St. Ange K, Fareed J, hoppensteadt D, Jeske W, Kouta A, Chi L, Jin C, Yao Y, Linhardt RJ, Clin. Appl. Thromb. Hemost 2017, 23, 542–553. - PubMed

Publication types

LinkOut - more resources