Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases: Successes, Failures, and Unexpected Progress Made in Organic Synthesis

Abstract

This account describes our efforts aimed toward the discovery of original glycomimetics that target protein misfolding to fight rare diseases, with a focus on cystic fibrosis and Gaucher disease. The pursuit of this goal has led to promising leads and strategies, with the first description of a multivalent effect for correcting protein-folding defects in cells, and has also driven unexpected progress in synthetic methodology.

1 Introduction

2 The Therapeutic Targets: Challenges and Stakes

2.1 Glycosphingolipid Lysosomal Storage Disorders

2.2 Cystic Fibrosis

3 Synthetic Targets Met, Potent Leads Gained

3.1 Synthetic Targets Met

3.2 A First Detour via a Substrate Reduction Therapy Approach

3.3 Potent Leads Gained

4 Synthetic Targets Missed, Synthetic Progress Gained

4.1 A New Domino Reaction

4.2 Extending the Scope of C–H Amination

4.3 A New Versatile Amino Protecting Group

5 Multivalency: A New and Promising Approach

5.1 How It Began

5.2 Gaucher Disease

5.3 Cystic Fibrosis

6 Conclusion

Key words

carbohydrates - tandem reactions - C–H functionalization - multivalency - glycosidases

• References

• 1 From: Jacob F. The Statue Within: An Autobiography . Cold Spring Harbor Laboratory Press; Woodbury: 1988. The original quotation in French is: ‘J’aime les idées fixes à condition d’en changer’
• 2 Ellgaard L, Helenius A. Nat. Rev. Mol. Cell Biol. 2003; 4: 181
• 3 Campioni S, Monsellier E, Chiti F In Protein Misfolding Diseases: Current and Emerging Principles and Therapies . Ramirez-Alvarado M, Kelly JW, Dobson CM. Wiley; Hoboken: 2010: 3-20
• 4a Cohen FE, Kelly JW. Nature 2003; 426: 905
• 4b Gavrin LK, Denny RA, Saiah E. J. Med. Chem. 2012; 55: 10823
• 4c Gomes CM. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2012; 12: 2460
• 5 Norez C, Noel S, Wilke M, Bijvelds M, Jorna H, Melin P, DeJonge H, Becq F. FEBS Lett. 2006; 580: 2081
• 6a Tabcharani JA, Chang XB, Riordan JR, Hanrahan JW. Nature 1991; 352: 628
• 6b Gadsby DC, Nairn AC. Physiol. Rev. 1999; 79: S77
• 6c Kartner N, Augustinas O, Jensen TJ, Naismith AL, Riordan JR. Nat. Genet. 1992; 1: 321
• 7 Fan J.-Q, Ishii S, Asano N, Suzuki Y. Nat. Med. 1999; 5: 112

For recent reviews, see:
• 8a Winchester B, Vellodi A, Young E. Biochem. Soc. Trans. 2000; 28: 150
• 8b Gregersen N. J. Inherit. Metab. Dis. 2006; 29: 456
• 8c Kolter T, Sandhoff K. Biochim. Biophys. Acta 2006; 1758: 2057
• 8d Raas-Rothshild A, Pankova-Kholmyansky I, Kacher Y, Futerman AH. Glycoconjugate J. 2004; 21: 295
• 8e Wennekes T, van den Berg RJ. B. H. N, Boot RG, van der Marel GA, Overkleeft HS, Aerts JM. F. G. Angew. Chem. Int. Ed. 2009; 48: 8848
• 8f Platt FM, Boland B, van der Spoel AC. J. Cell Biol. 2012; 199: 723
• 8g Grabowski GA. Hematology Am. Soc. Hematol. Educ. Program 2012; 13 ; doi: 10.1182/asheducation-2012.1.13
• 9a Fan J.-Q. In Iminosugars: From Synthesis to Therapeutic Applications . Compain P, Martin OR. Wiley-VCH; Weinheim: 2007: 225
• 9b Fan J.-Q. Trends Pharmacol. Sci. 2003; 24: 355
• 9c Fan J.-Q. Biol. Chem. 2008; 389: 1
• 9d Yu Z, Sawkar AR, Kelly JW. FEBS J. 2007; 274: 4944
• 9e Suzuki Y, Ogawa S, Sakakibara Y. Perspect. Med. Chem. 2009; 3: 7
• 9f Parenti G. EMBO Mol. Med. 2009; 1: 268
• 9g Desnick RJ. J. Inherit. Metab. Dis. 2004; 27: 385
• 9h Beck M. Expert Opin. Emerging Drugs 2010; 15: 495
• 9i Sawkar AR, D’Haeze W, Kelly JW. Cell Mol. Life Sci. 2006; 63: 1179
• 9j Valenzano KJ, Khanna R, Powe AC. Jr, Boyd R, Lee G, Flanagan JJ, Benjamin ER. Assay Drug Dev. Technol. 2011; 9: 213
• 9k Wrodnigg TM, Stütz AE. Curr. Enzyme Inhib. 2012; 8: 47
• 10a Benito JM, García Fernández JM, Ortiz Mellet C. Expert Opin. Ther. Pat. 2011; 21: 885
• 10b Boyd RE, Lee G, Rybczynski P, Benjamin ER, Khanna R, Wustman BA, Valenzano KJ. J. Med. Chem. 2013; 56: 2705
• 10c Trapero A, Llebaria A. Future Med. Chem. 2013; 5: 573
• 10d Compain P, Desvergnes V, Liautard V, Pillard C, Toumieux S In Iminosugars: From Synthesis to Therapeutic Applications . Compain P, Martin OR. Wiley-VCH; Weinheim: 2007: 327
• 11 For examples, see: Bols M, Lillelund VH, Jensen HH, Liang X. Chem. Rev. 2002; 102: 515
• 12a Sears P, Wong C.-H. Angew. Chem. Int. Ed. 1999; 38: 2300
• 12b Compain P, Martin OR. Bioorg. Med. Chem. 2001; 9: 3077
• 12c Ernst B, Magnani JL. Nat. Rev. Drug Discovery 2009; 8: 661
• 12d Koester DC, Dennis C, Holkenbrink A, Werz DB. Synthesis 2010; 3217
• 12e Carbohydrate Mimics: Concepts and Methods . Chapleur Y. Wiley-VCH; Weinheim: 1998
• 13 Quoted from: Smit WA, Bochkov AF, Caple R. Organic Synthesis: The Science Behind the Art. Royal Society of Chemistry; Cambridge: 1998
• 14 Hoffmann R. J. Aesth. Art Crit. 1990; 48: 191
• 15a Compain P, Desvergnes V, Ollivier C, Robert F, Suzenet F, Barboiu M, Belmont P, Blériot Y, Bolze F, Bouquillon S, Bourguet E, Braida B, Constantieux T, Désaubry L, Dupont D, Gastaldi S, Jérome F, Legoupy S, Marat X, Migaud M, Moitessier N, Papot S, Peri F, Petit M, Py S, Schulz E, Tranoy-Opalinski I, Vauzeilles B, Vayron P, Vergnes L, Vidal S, Wilmouth S. New J. Chem. 2006; 30: 823
• 15b Compain P. Actual. Chim. 2003; ( 263) 129
• 16 Stütz AE. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond. Wiley-VCH; Weinheim: 1999
• 17 Compain P, Martin OR. Iminosugars: From Synthesis to Therapeutic Applications. Wiley-VCH; Weinheim: 2007
• 18 Nicolaou KC, Vourloumis D, Wissinger N, Baran PS. Angew. Chem. Int. Ed. 2000; 39: 44
• 19a Fabrega S, Durand P, Codogno P, Bauvy C, Delomenie C, Henrissat B, Martin BM, McKinney C, Ginns EI, Mornon JP, Lehn P. Glycobiology 2000; 10: 1217
• 19b Fabrega S, Durand P, Mornon JP, Lehn P. J. Soc. Biol. 2002; 196: 151
• 19c Davies C, Henrissat B. Structure (Cambridge, MA) 1995; 3: 853
• 20a Special issue: Gaucher’s Disease, Baillières Clin. Haematol. 1997; 10: 621
• 20b Beutler E, Grabowski G In The Metabolic and Molecular Basis of Inherited Diseases . Scrivener C, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B. McGraw-Hill; New York: 2001. 8th ed. 3635
• 20c Butters TD. Curr. Opin. Chem. Biol. 2007; 11: 412
• 21 Meikle PJ, Hopwood JJ, Clague AE, Carey WF. JAMA, J. Amer. Med. Assoc. 1999; 281: 249
• 22 Horowitz M, Zimran A. Hum. Mutat. 1994; 3: 1
• 23a Butters TD In Iminosugars: from Synthesis to Therapeutic Applications . Compain P, Martin OR. Wiley-VCH; Weinheim: 2007
• 23b Aerts JM, Hollak C, Boot R, Groener A. Philos. Trans. R. Soc., B 2003; 358: 905
• 24a Beck M. Hum. Genet. 2007; 121: 1
• 24b Futerman AH, Sussman JL, Horowitz M, Silman I, Zimran A. Trends Pharmacol. Sci. 2004; 25: 147
• 24c Platt FM. Glycobiology 2005; 15: 43R
• 24d Mehta A. Acta Paediatrica 2008; 97: 83
• 24e Boustany RM. N. Nat. Rev. Neurol. 2013; 9: 583
• 24f van Gelder CM, Vollebregt AA. M, Plug I, van der Ploeg AT, Reuser AJ. J. Expert Opin. Pharmacother. 2012; 13: 2281
• 25a Wraith JE. J. Inherit. Metab. Dis. 2006; 29: 442
• 25b Rohrbach M, Clarke JT. R. Drugs 2007; 67: 2697
• 25c Ohashi T. Pediatr. Endocrinol. Rev. 2012; 10: 26
• 25d Lachmann RH. Curr. Opin. Pediatr. 2011; 23: 588
• 26a Butters TD, Dwek RA, Platt FM. Chem. Rev. 2000; 100: 4683
• 26b Lachmann RH, Platt FM. Expert Opin. Invest. Drugs 2001; 10: 455
• 26c Platt FM, Jeyakumar M, Andersson U, Heare T, Dwek RA, Butters TD. Phil. Trans. R. Soc., B 2003; 358: 947
• 26d Platt FM, Jeyakumar M. Acta Paediatrica 2008; 97: 88
• 27 Butters TD. Exp. Opin. Pharmacother. 2007; 8: 427
• 28 Beutler E. Mol. Genet. Metab. 2006; 88: 208
• 29 Smid BE, Aerts JM. F. G, Boot RG, Linthorst GE, Hollak CE. M. Expert. Opin. Invest. Drugs 2010; 19: 1367
• 30 Parenti G, Pignata C, Vajro P, Salerno MC. Int. J. Mol. Med. 2013; 31: 11
• 31a Yam GH.-F, Zuber C, Roth J. FASEB J. 2005; 19: 12
• 31b Kornhaber GJ, Tropak MB, Maegawa GH, Tuske SJ, Coales SJ, Mahuran DJ, Hamuro Y. ChemBioChem 2008; 9: 2643
• 31c Lieberman RL, Wustman BA, Huertas P, Powe AC, Pine CW. Nat. Chem. Biol. 2007; 3: 101
• 31d Steet RA, Chung S, Wustman B, Powe A, Do H, Kornfeld SA. Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 13813
• 31e Schmitz M, Alfalah M, Aerts JM. F. G, Naim HY, Zimmer K.-P. Int. J. Biochem. Cell Biol. 2005; 37: 2310
• 31f Sawkar AR, Schmitz M, Zimmer K.-P, Reczek D, Edmunds T, Balch WE, Kelly JW. ACS Chem. Biol. 2006; 1: 235
• 32 Wei RR, Hughes H, Boucher S, Bird JJ, Guziewicz N, Van Patten SM, Qiu H, Qun Pan C, Edmunds T. J. Biol. Chem. 2011; 286: 299
• 33a Babajani G, Tropak MB, Mahuran DJ, Kermode AR. Mol. Genet. Metab. 2012; 106: 323
• 33b Tang L, Coales SJ, Morrow JA, Edmunds T, Hamuro Y. ChemBioChem 2012; 13: 2243

For discussions on the so-called threshold theory, see:
• 34a Kolter T, Wendeler M. ChemBioChem 2003; 4: 260
• 34b Conzelmann E, Sandhoff K. Dev. Neurosci. (Amsterdam) 1983; 6: 58
• 34c Leinekugel P, Michel S, Conzelmann E, Sandhoff K. Hum. Genet. 1992; 88: 513
• 35a Horne G, Wilson FX, Tinsley J, Williams DH, Storer R. Drug Discovery Today 2011; 16: 107
• 35b Germain DP, Fan J.-Q. Int. J. Clin. Pharmacol. Ther. 2009; 47: S111
• 36a Martin OR, Xie F, Liu L. Tetrahedron Lett. 1995; 36: 4027
• 36b Asano N, Ikeda K, Yasuda K, Kizu H, Kameda Y, Kato A, Okamato T, Ishii S, Compain P, Martin OR, Fan J.-Q. Glycoconjugate J. 1999; 16: S156
• 36c Asano N, Ishii S, Kizu H, Ikeda K, Yasuda K, Kato A, Martin OR, Fan J.-Q. Eur. J. Biochem. 2000; 267: 4179
• 37 Sawkar AR, Cheng W.-C, Beutler E, Wong C.-H, Balch WE, Kelly JW. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 15428
• 38 Hodson ME. Respiration 2000; 67: 595
• 39a Rosenstein BJ, Cutting GR. J. Pediatr. (N. Y., NY U. S.) 1998; 132: 589
• 39b Hamosh A, Fitz-Simmons SC, Macek MJr, Knowles MR, Rosenstein BJ, Cutting GR. J. Pediatr. (N. Y., NY U. S.) 1998; 132: 255
• 39c Farell PM. J. Cyst. Fibros. 2008; 7: 450
• 40 Lubamba B, Dhooghe B, Noel S, Leal T. Clin. Biochem. 2012; 45: 1132
• 41 Davis PB. Am. J. Respir. Crit. Care Med. 2006; 173: 475
• 42a Becq F, Mall MA, Sheppard DN, Conese M, Zegarra-Moran O. J. Cyst. Fibros. 2011; 10: S129
• 42b Birault V, Solari R, Hanrahan J, Thomas DY. Curr. Opin. Chem. Biol. 2013; 17: 353
• 42c Molinski S, Eckford PD. W, Pasyk S, Ahmadi S, Chin S, Bear CE. Front. Pharmacol. 2012; 3: 160 ; doi: 10.3389/fphar.2012.00160
• 42d Merk D, Schubert-Zsilavecz M. Expert Opin. Drug Discovery 2013; 8: 691
• 42e Becq F, Mettey Y. Expert Opin. Ther. Patents 2004; 14: 1465
• 42f Hanrahan JW, Sampson HM, Thomas DY. Trends Pharmacol. Sci. 2013; 34: 119
• 42g Pedemonte N, Galietta LJ. V. Front. Pharmacol. 2012; 3: 175 ; doi: 10.3389/fphar.2012.00175
• 42h Rowe SM, Verkman AS. Cold Spring Harb. Perspect. Med. 2013; 3: a009761
• 42i Galietta LJ. V. Pediatr. Drugs 2013; 15: 393 ; doi: 10.1007/s40272-013-0035-3
• 43 Wilschanski M. Discov. Med. 2013; 15: 127
• 44 Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ. Nature 1992; 358: 761
• 45 Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ. V, Verkman AS. J. Clin. Invest. 2005; 115: 2564
• 46a Pind S, Riordan JR, Williams DB. J. Biol. Chem. 1994; 269: 12784
• 46b Helenius A, Aebi M. Annu. Rev. Biochem. 2004; 73: 1019
• 46c Ware FE, Vassilakos A, Peterson PA, Jackson MR, Lehrman MA, Williams DB. J. Biol. Chem. 1995; 270: 4697
• 47a Noel S, Faveau C, Norez C, Rogier C, Mettey Y, Becq F. J. Pharmacol. Exp. Ther. 2006; 319: 349
• 47b Norez C, Antigny F, Noel S, Vandebrouck C, Becq F. Am. J. Respir. Cell. Mol. Biol. 2009; 41: 217
• 48 For a review on imino-C-glycosides, see: Compain P, Chagnault V, Martin OR. Tetrahedron: Asymmetry 2009; 20: 672
• 49a Godin G, Compain P, Masson G, Martin OR. J. Org. Chem. 2002; 67: 6960
• 49b Masson G, Compain P, Martin OR. Org. Lett. 2000; 2: 2971
• 49c Godin G, Compain P, Martin OR, Ikeda K, Yu L, Asano N. Bioorg. Med. Chem. Lett. 2004; 14: 5991
• 50 Godin G, Compain P, Martin OR. Org. Lett. 2003; 5: 3269
• 51 Godin G, Compain P, Martin OR. Synlett 2003; 2065
• 52 Compain P, Martin OR, Boucheron C, Godin G, Yu L, Ikeda K, Asano N. ChemBioChem 2006; 7: 1356

For improved syntheses of α-1-C-alkyl-iminoxylitol derivatives, see:
• 53a Oulaïdi F, Gallienne E, Compain P, Martin OR. Tetrahedron: Asymmetry 2011; 22: 609
• 53b Biela A, Oulaïdi F, Gallienne E, Górecki M, Frelek J, Martin OR. Tetrahedron 2013; 69: 3348
• 54 Boucheron C, Compain P, Martin OR. Tetrahedron Lett. 2006; 47: 3081
• 55 Boucheron C, Desvergnes V, Compain P, Martin OR, Lavi A, Mackeen M, Wormald MR, Dwek RA, Butters TD. Tetrahedron: Asymmetry 2005; 16: 1747
• 56 Boucheron C, Toumieux S, Compain P, Martin OR, Ikeda K, Asano N. Carbohydr. Res. 2007; 342: 1960
• 57a Butters TD, van den Broek LA. G. M, Fleet GW. J, Krulle TM, Wormald MR, Dwek RA, Platt FM. Tetrahedron: Asymmetry 2000; 11: 113
• 57b Butters TD, Dwek RA, Platt FM. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2003; 3: 561
• 58 The results obtained for the O-alkylated derivatives can be explained, in part, by the fact that the C2-hydroxyl group of the DNJ core is important for glycosylceramide synthase inhibition, as recently demonstrated; see: van den Berg RJ. B. H. N, Wennekes T, Ghisaidoobe A, Donker-Koopman WE, Strijland A, Boot RG, van der Marel GA, Aerts JM. F. G, Overkleeft HS. ACS Med. Chem. Lett. 2011; 2: 519
• 59 Yu L, Ikeda K, Kato A, Adachi I, Godin G, Compain P, Martin OR, Asano N. Bioorg. Med. Chem. 2006; 14: 7736
• 60 Bordier A, Compain P, Martin OR, Ikeda K, Asano N. Tetrahedron: Asymmetry 2003; 14: 47
• 61 In 2005, Fan and co-workers reported the discovery of 6-C-nonylisofagomine, a very potent GCase inhibitor (IC₅₀ = 0.6 nM), see: Zhu X, Sheth KA, Li S, Chang H.-H, Fan J.-Q. Angew. Chem. Int. Ed. 2005; 44: 7450
• 62 Schönemann W, Gallienne E, Compain P, Ikeda K, Asano N, Martin OR. Bioorg. Med. Chem. 2010; 18: 2645
• 63 Mellor HR, Platt FM, Dwek RA, Butters TD. Biochem. J. 2003; 374: 307
• 64 Oulaïdi F, Front-Deschamps S, Gallienne E, Lesellier E, Ikeda K, Asano N, Compain P, Martin OR. ChemMedChem 2011; 6: 353
• 65 The IC₅₀ value for N-nonyl-DIX is 1500 nM; see ref. 62. The estimated IC₅₀ value for N-hexyl DIX is therefore > 1500 nM.
• 66a Nocquet P.-A, Hazelard D, Compain P. Eur. J. Org. Chem. 2011; 6619
• 66b Nocquet P.-A, Hazelard D, Compain P. Tetrahedron 2012; 68: 4117
• 67 To our knowledge, only one example of the formation of a cyclobutane by a Dieckmann reaction has been reported in the literature, but no mention is given of the yield obtained; see: Chande MS, Suryanarayan V. Tetrahedron Lett. 2002; 43: 5173
• 68a Hoye TR, Dvornikovs V, Sizova E. Org. Lett. 2006; 8: 5191
• 68b Rietsch V, Miesch L, Yamashita D, Miesch M. Eur. J. Org. Chem. 2010; 6944

For recent examples, see:
• 69a Kim S.-Y, Park H.-B, Cho J.-H, Yoo K.-H, Oh C.-H. Bioorg. Med. Chem. Lett. 2009; 19: 2558
• 69b Cianchetta G, Mannhold R, Cruciani G, Baroni M, Cecchetti V. J. Med. Chem. 2004; 47: 3193
• 69c Guo Z, Orth P, Wong S.-C, Lavey BJ, Shih N.-Y, Niu X, Lundell DJ, Madison V, Kozlowski JA. Bioorg. Med. Chem. Lett. 2009; 19: 54
• 70a Couty F, Evano G. Synlett 2009; 3053
• 70b Van Brabandt W, Van Landeghem R, De Kimpe N. Org. Lett. 2006; 8: 1105
• 70c Blakemore DC, Chiva J.-Y, Thistlethwaite I. Synlett 2011; 1101
• 70d Mollet K, Catak S, Waroquier M, Van Speybroeck V, D’hooghe M, De Kimpe N. J. Org. Chem. 2011; 76: 8364
• 70e Mollet K, Broeckx L, D’hooghe M, De Kimpe N. Heterocycles 2012; 84: 431
• 71 Nocquet, P.-A.; Hazelard, D.; Compain, P. unpublished results.
• 72 For a synthesis of the carbasugar moiety of 28 by way of a stereoselective SmI₂-mediated aldehyde–alkene cyclization, see: Nocquet P.-A, Hazelard D, Gruntz G, Compain P. J. Org. Chem. 2013; 78: 6751
• 73 For examples of intramolecular ring-opening reactions of N-alkylated azetidines with amines, see: Vargas-Sanchez M, Couty F, Evano G, Prim D, Marrot J. Org. Lett. 2005; 7: 5861
• 74 Espino CG, Du Bois J. Angew. Chem. Int. Ed. 2001; 40: 598
• 75 Espino CG, Wehn PM, Chow J, Du Bois J. J. Am. Chem. Soc. 2001; 123: 6935
• 76 Breslow R, Gellman SH. J. Am. Chem. Soc. 1983; 105: 6728
• 77a Dauban P, Sanière L, Tarrade RH, Dodd R. J. Am. Chem. Soc. 2001; 123: 7707
• 77b Yu X.-Q, Huang J.-S, Zhou X.-G, Che C.-M. Org. Lett. 2000; 2: 2233

For comprehensive reviews, see:
• 78a Du Bois J. Chemtracts 2005; 18: 1
• 78b Espino CG, Du Bois J In Modern Rhodium-Catalyzed Organic Reaction . Evans PA. Wiley-VCH; Weinheim: 2005: 379
• 78c Müller P, Fruit C. Chem. Rev. 2003; 103: 2905
• 78d Dauban P, Dodd RH. Synlett 2003; 1571
• 78e Dauban P, Dodd R In Amino Group Chemistry: From Synthesis to the Life Sciences . Ricci A. Wiley-VCH; Weinheim: 2007: 55
• 78f Dick AR, Sanford MS. Tetrahedron 2006; 62: 2439
• 78g Li Z, He C. Eur. J. Org. Chem. 2006; 4313
• 78h Davies HM. L, Long MS. Angew. Chem. Int. Ed. 2005; 44: 3518
• 78i Collet F, Dodd RH, Dauban P. Chem. Commun. 2009; 5061
• 78j Compain P, Toumieux P In Targets in Heterocyclic Systems: Chemistry and Properties . Vol. 11. Attanasi OA, Spinelli D. Royal Society of Chemistry; Cambridge: 2007: 338
• 78k Collet F, Lescot C, Dauban P. Chem. Soc. Rev. 2011; 40: 1926
• 78l Dequirez G, Pons V, Dauban P. Angew. Chem. Int. Ed. 2012; 51: 7384
• 78m Roizen JL, Harvey ME, Du Bois J. Acc. Chem. Res. 2012; 45: 911
• 79a Meléndez RS, Lubell WD. Tetrahedron 2003; 59: 2581
• 79b Bower JF, Rujirawanich J, Gallagher T. Org. Biomol. Chem. 2010; 8: 1505
• 80 For a review on amino C-glycoside synthesis, see: Xie J. Recent Res. Dev. Org. Chem. 1999; 3: 505
• 81 Granier T, Vasella A. Helv. Chim. Acta 1998; 81: 865
• 82 Flemming JJ, Fiori KW, Du Bois J. J. Am. Chem. Soc. 2003; 125: 2028
• 83 Toumieux S, Compain P, Martin OR. Tetrahedron Lett. 2005; 46: 4731
• 84 The NMR spectrum of the crude product after C–H amination appeared to indicate the presence of a spirooxathiazolidine in equilibrium with the corresponding open-chain imine form. The crude product was treated directly with Boc₂O in pyridine to afford, after a simple filtration on silica gel, compound 43 as a single diastereoisomer. See ref. 83.
• 85a Wardrop DJ, Zhang W, Fritz J. Org. Lett. 2002; 4: 489
• 85b Malatesta V, Ingold KU. J. Am. Chem. Soc. 1981; 103: 609
• 86 Toumieux S, Compain P, Martin OR, Selkti M. Org. Lett. 2006; 8: 4493
• 87a Johnson F. Chem. Rev. 1968; 68: 375
• 87b Hoffman RW. Chem. Rev. 1989; 89: 1841
• 87c Kuznetsov NY, Khrustalev VN, Godovikov IA, Bubnov YN. Eur. J. Org. Chem. 2006; 113
• 87d Cariou CA. M, Snaith JS. Org. Biomol. Chem. 2006; 4: 51
• 87e Jourdant A, Zhu J. Tetrahedron Lett. 2000; 41: 7033
• 88 Morin MS. T, Toumieux S, Compain P, Peyrat S, Kalinowska-Tlusik J. Tetrahedron Lett. 2007; 48: 8531
• 89 Toumieux S, Compain P, Martin OR. J. Org. Chem. 2008; 73: 2155
• 90 Wyszynski FJ, Thompson AL, Davis BG. Org. Biomol. Chem. 2010; 8: 4246
• 91a Milczek E, Boudet N, Blakey S. Angew. Chem. Int. Ed. 2008; 47: 6825
• 91b Trost BM, O’Boyle BM, Torres W, Ameriks MK. Chem. Eur. J. 2011; 17: 7890
• 92 Ranatunga S, Del Valle JR. Tetrahedron Lett. 2009; 50: 2464
• 93 Rodríguez-Lucena D, Morin MS. T, Compain P. Lett. Org. Chem. 2011; 8: 155
• 94 For a review on olefin metathesis of amine-containing systems, see: Compain P. Adv. Synth. Catal. 2007; 349: 1829
• 95 Cipolla L, Palma A, La Ferla B, Nicotra F. J. Chem. Soc., Perkin Trans. 1 2002; 2161
• 96 Decroocq C, Mamani Laparra L, Rodríguez-Lucena D, Compain P. J. Carbohydr. Chem. 2011; 30: 559
• 97 Iehl J, Nierengarten J.-F. Chem. Eur. J. 2009; 15: 7306

For the evaluation of multivalent glycosylated fullerenes as glycosyltransferase inhibitors or lectin ligands, see:
• 98a Cecioni S, Oerthel V, Iehl J, Holler M, Goyard D, Praly J.-P, Imberty A, Nierengarten J.-F, Vidal S. Chem. Eur. J. 2011; 17: 3252
• 98b Durka M, Buffet K, Iehl J, Holler M, Nierengarten J.-F, Vincent SP. Chem. Eur. J. 2012; 18: 641
• 98c Sánchez-Navarro M, Muñoz A, Illescas BM, Rojo J, Martín N. Chem. Eur. J. 2011; 17: 766
• 99a Lahmann M. Top. Curr. Chem. 2009; 288: 17
• 99b Deniaud D, Julienne K, Gouin SG. Org. Biomol. Chem. 2011; 9: 966
• 99c Pieters RJ. Org. Biomol. Chem. 2009; 7: 2013
• 99d Imberty A, Chabre Y, Roy R. Chem. Eur. J. 2008; 14: 7490
• 99e Chabre YM, Roy R. Adv. Carbohydr. Chem. Biochem. 2010; 63: 165
• 99f Hartmann M, Lindhorst TK. Eur. J. Org. Chem. 2011; 3583
• 99g Jayaraman N. Chem. Soc. Rev. 2009; 38: 3463
• 99h Martínez A, Ortiz Mellet C, García Fernández JM. Chem. Soc. Rev. 2013; 42: 4746
• 99i Chabre YM, Roy R. Chem. Soc. Rev. 2013; 42: 4657
• 99j Choi S.-K. Synthetic Multivalent Molecules: Concepts and Biomedical Applications. Wiley-VCH; Weinheim: 2004
• 100 Kitov PI, Sadowska JM, Mulvey G, Armstrong GD, Ling H, Pannu NS, Read RJ, Bundle DR. Nature 2000; 403: 669
• 101a Wennekes T, van der Berg RJ. B. H. N, Bonger KM, Donker-Koopman WE, Ghisaidoobe A, van der Marel GA, Strijland A, Aerts JM. F. G, Overkleeft HS. Tetrahedron: Asymmetry 2009; 20: 836
• 101b Johns BA, Johnson CR. Tetrahedron Lett. 1998; 39: 749
• 101c Lohse A, Jensen KB, Lundgren K, Bols M. Bioorg. Med. Chem. 1999; 7: 1965
• 101d McCort Y, Sanière M, Le Merrer Y. Tetrahedron 2003; 59: 2693
• 102a Mammen M, Choi S.-K, Withesides GM. Angew. Chem. Int. Ed. 1998; 37: 2754
• 102b Gestwicki JE, Cairo CW, Strong LE, Oetjen KA, Kiessling LL. J. Am. Chem. Soc. 2002; 124: 14922
• 102c Kiessling L, Gestwicki JE, Strong LE. Curr. Opin. Chem. Biol. 2000; 4: 696
• 103 Diot J, Garcia-Moreno MI, Gouin SG, Ortiz Mellet C, Haupt K, Kovensky J. Org. Biomol. Chem. 2009; 7: 357
• 104 Compain P, Decroocq C, Iehl J, Holler M, Hazelard D, Mena Barragán T, Ortiz Mellet C, Nierengarten J.-F. Angew. Chem. Int. Ed. 2010; 49: 5753
• 105 Decroocq C, Rodríguez-Lucena D, Russo V, Mena Barragán T, Ortiz Mellet C, Compain P. Chem. Eur. J. 2011; 17: 13825

For studies on the mechanisms underlying the multivalent effect in glycosidase inhibition, see:
• 106a Decroocq C, Joosten A, Sergent R, Mena Barragán T, Ortiz Mellet C, Compain P. ChemBioChem 2013; 14: 2038
• 106b Rísquez-Cuadro R, García Fernández JM, Nierengarten J.-F, Ortiz Mellet C. Chem. Eur. J. 2013; 19: 16791
• 106c Brissonet Y, Ortiz Mellet C, Morandat S, Garcia-Moreno MI, Deniaud D, Matthews SE, Vidal S, Sestak S, El Kirat K, Gouin SG. J. Am. Chem. Soc. 2013; 135: 18427
• 107 Decroocq C, Rodríguez-Lucena D, Ikeda K, Asano N, Compain P. ChemBioChem 2012; 13: 661
• 108 Joosten A, Decroocq C, de Sousa J, Schneider J, Etamé E, Bodlenner A, Butters TD, Compain P. ChemBioChem 2014; 15: 309
• 109 K _i values were determined on human placental GCase. The multivalent effect determined for 81 was found to be lower by one order of magnitude than the one initially measured in our first preliminary study with ceredase (see Ref. 107).
• 110 Compain P, Decroocq C, Joosten A, de Sousa J, Rodríguez-Lucena D, Butters TD, Bertrand J, Clément R, Boinot C, Becq F, Norez C. ChemBioChem 2013; 14: 2050

Overkleeft and co-workers have recently used α-1-C-nonyl-iminoxylitol 14a as a chemical tool to elucidate the metabolism of glucosylceramide, see:
• 111a Wennekes T, van den Berg RJ. B. H. N, Boltje TJ, Donker-Koopman WE, Kuijper B, van der Marel GA, Strijland A, Verhagen CP, Aerts JM. F. G, Overkleeft HS. Eur. J. Org. Chem. 2010; 1258
• 111b Dekker N, Voorn-Brouwer T, Verhoek M, Wennekes T, Narayan RS, Speijer D, Hollak CE. M, Overkleeft HS, Boot RG, Aerts JM. F. G. Blood Cells, Mol., Dis. 2011; 46: 19
• 112 Schönemann W, Gallienne E, Ikeda-Obatake K, Asano N, Nakagawa S, Kato A, Adachi I, Górecki M, Frelek J, Martin OR. ChemMedChem 2013; 8: 1805
• 113 Very recently, it was demonstrated that CFTR correctors can also correct protein-folding diseases other than cystic fibrosis, see: Sampson HM, Lam H, Chen P.-C, Zhang D, Mottillo C, Mirza M, Qasim K, Shrier A, Shyng S.-L, Hanrahan JW, Thomas DY. Orphanet J. Rare Dis. 2013; 8: 11