Download PDF
Synthesis 2021; 53(22): 4263-4271
DOI: 10.1055/a-1509-5904
special topic
Special Issue dedicated to Prof. Sarah Reisman, recipient of the 2019 Dr. Margaret Faul Women in Chemistry Award

Catalytic Synthesis of PEGylated EGCG Conjugates that Disaggregate Alzheimer’s Tau

Anton El Khoury
,
Paul M. Seidler
,
David S. Eisenberg∗
,
Patrick G. Harran  ∗
Funding provided by the Donald J. and Jane M. Cram Endowment (to P.H.), the NIH (R56 AG070895 to D.E.), and the HHMI (D.E.).
› Further Information
    Permissions and Reprints All articles of this category


Abstract

The naturally occurring flavonoid (–)-epigallocatechin gallate (EGCG) is a potent disaggregant of tau fibrils. Guided by the recent cryo-electron microscopy (cryoEM) structure of EGCG bound to fibrils of tau derived from an Alzheimer’s brain donor, methods to site-specifically modify the EGCG D-ring with aminoPEGylated linkers are reported. The resultant molecules inhibit tau fibril seeding by Alzheimer’s brain extracts. Formulations of aminoPEGylated EGCG conjugated to the (quasi)-brain-penetrant nanoparticle Ferumoxytol inhibit seeding by AD-tau with linker length affecting activity. The protecting group-free catalytic cycloaddition of amino azides to mono-propargylated EGCG described here provides a blueprint for access to stable nanoparticulate forms of EGCG potentially useful as therapeutics to eliminate Alzheimer’s-related tau tangles.

Key words

(–)-epigallocatechin gallate - Alzheimer’s disease - tau disaggregation - nanoparticle conjugation - click reaction - TBTA

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1509-5904.
  • Supporting Information


Publication History

Received: 16 April 2021

Accepted after revision: 17 May 2021

Accepted Manuscript online:
17 May 2021

Article published online:
08 June 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Present address: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, 1985 Zonal Ave, Los Angeles CA 90089-9121, USA.
  • 2 Alzheimers Dement. 2020; 16: 391
    CrossrefPubMed
  • 3 Gouras GK, Olsson TT, Hansson O. Neurotherapeutics 2015; 12: 3
    CrossrefPubMed
  • 4 Murray ME, Lowe VJ, Graff-Radford NR, Liesinger AM, Cannon A, Przybelski SA, Rawal B, Parisi JE, Petersen RC, Kantarci K, Ross OA, Duara R, Knopman DS, Jack CR, Dickson DW. Brain 2015; 138: 1370
    CrossrefPubMed
    • 5a Bieschke J, Russ J, Friedrich RP, Ehrnhoefer DE, Wobst H, Neugebauer K, Wanker EE. Proc. Natl. Acad. Sci. U. S. A. 2010; 107: 7710
      CrossrefPubMed
    • 5b Debnath K, Shekhar S, Kumar V, Jana NR, Jana NR. ACS Appl. Mater. Interfaces 2016; 8: 20309
      CrossrefPubMed
  • 6 Wobst HJ, Sharma A, Diamond MI, Wanker EE, Bieschke J. FEBS Lett. 2015; 589: 77
    CrossrefPubMed
    • 7a Seidler PM, Boyer DR, Sawaya MR, Ge P, Shin WS, DeTure MA, Dickson DW, Jiang L, Eisenberg DS. bioRxiv 2020; preprint DOI: 10.1101/2020.05.29.124537.
    • 7b Sonawane SK, Chidambaram H, Boral D, Gorantla NV, Balmik AA, Dangi A, Ramasamy S, Marelli UK, Chinnathambi S. Sci. Rep. 2020; 10: 12579
      CrossrefPubMed
    • 8a Lu M, Cohen MH, Rieves D, Pazdur R. Am. J. Hematol. 2010; 85: 315
      PubMed
    • 8b Muldoon LL, Sàndor M, Pinkston KE, Neuwelt EA. Neurosurgery 2005; 57: 785
      CrossrefPubMed
    • 8c Neubert J, Wagner S, Kiwit J, Bräuer AU, Glumm J. Int. J. Nanomed. 2015; 10: 2033
      CrossrefPubMed
    • 8d Nguyen KL, Yoshida T, Kathuria-Prakash N, Zaki IH, Varallyay CG, Semple SI, Saouaf R, Rigsby CK, Stoumpos S, Whitehead KK, Griffin LM, Saloner D, Hope MD, Prince MR, Fogel MA, Schiebler ML, Roditi GH, Radjenovic A, Newby DE, Neuwelt EA, Bashir MR, Hu P, Paul Finn J. Radiology 2019; 293: 554
      CrossrefPubMed
  • 9 Wang J, Sun P, Wang Q, Zhang P, Wang Y, Zi C, Wang X, Sheng J. Cancer Cell Int. 2019; 19: 266
    CrossrefPubMed
  • 10 Yang Q, Sheng M, Henkelis JJ, Tu S, Wiensch E, Zhang H, Zhang Y, Tucker C, Ejeh DE. Org. Process Res. Dev. 2019; 23: 2210
    CrossrefPubMed
    • 11a Aufort M, Herscovici J, Bouhours P, Moreau N, Girard C. Bioorg. Med. Chem. Lett. 2008; 18: 1195
      CrossrefPubMed
    • 11b Dieterich DC, Lee JJ, Link AJ, Graumann J, Tirrell DA, Schuman EM. Nat. Protoc. 2007; 2: 532
      CrossrefPubMed
    • 11c Floros MC, Leão AL, Narine SS. BioMed Res. Int. 2014; Article ID 792901
      PubMed
    • 11d Lee W, Sarkar S, Pal R, Kim JY, Park H, Huynh PT, Bhise A, Bobba KN, Kim KI, Ha YS, Soni N, Kim W, Lee K, Jung JM, Rajkumar S, Lee KC, Yoo J. ACS Appl. Biomater. 2021; 4: 2544
    • 11e Sun P, Chen J, Liu J, Zhang K. Macromolecules 2017; 50: 1463
      Crossref
  • 12 Himo F, Lovell T, Hilgraf R, Rostovtsev VV, Noodleman L, Sharpless KB, Fokin VV. J. Am. Chem. Soc. 2005; 127: 210
    CrossrefPubMed
  • 13 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
    CrossrefPubMed
  • 14 Chan TR, Hilgraf R, Sharpless KB, Fokin VV. Org. Lett. 2004; 6: 2853
    CrossrefPubMed
  • 15 Madhusudanan KP, Sachdev K, Harrison DA, Kulshreshtha DK. Int. J. Mass Spectrom. Ion Processes 1984; 62: 289
    Crossref
  • 16 Jordheim M, Fossen T, Songstad J, Andersen ØM. J. Agric. Food Chem. 2007; 55: 8261
    CrossrefPubMed
    • 17a Sanders DW, Kaufmann SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC, Miller TM, Grinberg LT, Tolnay M, Seeley WW, Diamond MI. Neuron. 2014; 82: 1271
      CrossrefPubMed
    • 17b Seidler PM, Boyer DR, Murray KA, Yang TP, Bentzel M, Sawaya MR, Rosenberg G, Cascio D, Williams CK, Newell KL, Ghetti B, DeTure MA, Dickson DW, Vinters HV, Eisenberg DS. J. Biol. Chem. 2019; 294: 16451
      CrossrefPubMed
    • 18a Toth GB, Varallyay CG, Horvath A, Bashir MR, Choyke PL, Daldrup-Link HE, Dosa E, Finn JP, Gahramanov S, Harisinghani M, Macdougall I, Neuwelt A, Vasanawala SS, Ambady P, Barajas R, Cetas JS, Ciporen J, DeLoughery TJ, Doolittle ND, Fu R, Grinstead J, Guimaraes AR, Hamilton BE, Li X, McConnell HL, Muldoon LL, Nesbit G, Netto JP, Petterson D, Rooney WD, Schwartz D, Szidonya L, Neuwelt EA. Kidney Int. 2017; 92: 47
      CrossrefPubMed
    • 18b Enteshari Najafabadi R, Kazemipour N, Esmaeili A, Beheshti S, Nazifi S. BMC Pharmacol. Toxicol. 2018; 19: 59
      CrossrefPubMed
    • 19a He A, Guan X, Song H, Li S, Huang K. Food Biosci. 2020; 37: 100727
    • 19b Radhakrishnan R, Kulhari H, Pooja D, Gudem S, Bhargava S, Shukla R, Sistla R. Chem. Phys. Lipids 2016; 198: 51
      CrossrefPubMed
    • 19c Sanna V, Singh CK, Jashari R, Adhami VM, Chamcheu JC, Rady I, Sechi M, Mukhtar H, Siddiqui IA. Sci. Rep. 2017; 7: 41573
      CrossrefPubMed
    • 19d Smith A, Giunta B, Bickford PC, Fountain M, Tan J, Shytle RD. Int. J. Pharm. 2010; 389: 207
      CrossrefPubMed
    • 19e Zou L-Q, Peng S-F, Liu W, Gan L, Liu W-L, Liang R-H, Liu C-M, Niu J, Cao Y-L, Liu Z, Chen X. Food Res. Int. 2014; 64: 492
      CrossrefPubMed
  • 20 Tran F, Odell AV, Ward GE, Westwood NJ. Molecules 2013; 18: 11639
    CrossrefPubMed
  • 21 Friscourt F, Fahrni CJ, Boons GJ. J. Am. Chem. Soc. 2012; 134: 18809
    CrossrefPubMed
  • 22 Bertozzi CR, Bednarski MD. J. Org. Chem. 1991; 56: 4326
    Crossref
  • 23 Brauch S, Henze M, Osswald B, Naumann K, Wessjohann LA, Van Berkel SS, Westermann B. Org. Biomol. Chem. 2012; 10: 958
    CrossrefPubMed
  • 24 Wang H, Raghupathi KR, Zhuang J, Thayumanavan S. ACS Macro Lett. 2015; 4: 422
    CrossrefPubMed