Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Synthesis of a Novel Curcumin Derivative as a Potential Imaging Probe in Alzheimer’s Disease Imaging

Author(s): Alexander Sturzu, Sumbla Sheikh*, Hubert Kalbacher, Thomas Nägele, Christopher Weidenmaier, Bettina M. Wegenast-Braun, Nadine Schilling, Ulrike Ernemann and Stefan Heckl

Volume 16, Issue 8, 2019

Page: [723 - 731] Pages: 9

DOI: 10.2174/1567205016666190816130516

Price: $65

Abstract

Background: Curcumin has been of interest in the field of Alzheimer’s disease. Early studies on transgenic mice showed promising results in the reduction of amyloid plaques.However, curcumin is very poorly soluble in aqueous solutions and not easily accessible to coupling as it contains only phenolic groups as potential coupling sites. For these reasons only few imaging studies using curcumin bound as an ester were performed and curcumin is mainly used as nutritional supplement.

Methods: In the present study we produced an aminoethyl ether derivative of curcumin using a nucleophilic substitution reaction. This is a small modification and should not impact the properties of curcumin while introducing an easily accessible reactive amino group. This novel compound could be used to couple curcumin to other molecules using the standard methods of peptide synthesis. We studied the aminoethyl-curcumin compound and a tripeptide carrying this aminoethyl-curcumin and the fluorescent dye fluorescein (FITC-curcumin) in vitro on cell culture using confocal laser scanning microscopy and flow cytometry. Then these two substances were tested ex vivo on brain sections prepared from transgenic mice depicting Alzheimer-like β-amyloid plaques.

Results: In the in vitro CLSM microscopy and flow cytometry experiments we found dot-like unspecific uptake and only slight cytotoxicity correlating with this uptake. As these measurements were optimized for the use of fluorescein as dye we found that the curcumin at 488nm fluorescence excitation was not strong enough to use it as a fluorescence marker in these applications. In the ex vivo sections CLSM experiments both the aminoethyl-curcumin and the FITC-curcumin peptide bound specifically to β- amyloid plaques.

Conclusion: In conclusion we successfully produced a novel curcumin derivative which could easily be coupled to other imaging or therapeutic molecules as a sensor for amyloid plaques.

Keywords: Curcumin, Alzheimer's disease, cytometry, amyloid plaques, confocal laser scanning microscopy, human prostate cancer cell, antibiotics.

[1]
Lim, G.P.; Chu, T.; Yang, F.; Beech, W.; Frautschy, S.A.; Cole, G.M. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci., 21(21), 8370-8377. 2001
[http://dx.doi.org/10.1523/JNEUROSCI.21-21-08370.2001] [PMID: 11606625]
[2]
Ding, L.; Ma, S.; Lou, H.; Sun, L.; Ji, M. Synthesis and Biological Evaluation of Curcumin Derivatives with Water-Soluble Groups as Potential Antitumor Agents: An in vitro Investigation Using Tumor Cell Lines. Molecules, 20(12), 21501-21514. 2015
[http://dx.doi.org/10.3390/molecules201219772] [PMID: 26633344]
[3]
Safavy, A.; Raisch, K.P.; Mantena, S.; Sanford, L.L.; Sham, S.W.; Krishna, N.R. Design and development of water-soluble curcumin conjugates as potential anticancer agents. J. Med. Chem., 50(24), 6284-6288. 2007
[http://dx.doi.org/10.1021/jm700988f] [PMID: 17973470]
[4]
Ramsewak, R.S.; DeWitt, D.L.; Nair, M.G. Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I-III from Curcuma longa. Phytomedicine, 7(4), 303-308. 2000
[http://dx.doi.org/10.1016/S0944-7113(00)80048-3] [PMID: 10969724]
[5]
Cutrin, J.C.; Crich, S.G.; Burghelea, D.; Dastrù, W.; Aime, S. Curcumin/Gd loaded apoferritin: a novel “theranostic” agent to prevent hepatocellular damage in toxic induced acute hepatitis. Mol. Pharm., 10(5), 2079-2085. 2013
[http://dx.doi.org/10.1021/mp3006177] [PMID: 23548053]
[6]
Cheng, K.K.; Chan, P.S.; Fan, S.; Kwan, S.M.; Yeung, K.L.; Wáng, Y.X. Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer’s disease mice using magnetic resonance imaging (MRI). Biomaterials, 44, 155-172. 2015
[http://dx.doi.org/10.1016/j.biomaterials.2014.12.005] [PMID: 25617135]
[7]
Zhang, X.; Tian, Y.; Li, Z.; Tian, X.; Sun, H.; Liu, H. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer’s disease. J. Am. Chem. Soc., 135(44), 16397-16409. 2013
[http://dx.doi.org/10.1021/ja405239v] [PMID: 24116384]
[8]
Sagnou, M.; Benaki, D.; Triantis, C.; Tsotakos, T.; Psycharis, V.; Raptopoulou, C.P. Curcumin as the OO bidentate ligand in “2 + 1” complexes with the [M(CO)3]+ (M = Re, 99mTc) tricarbonyl core for radiodiagnostic applications. Inorg. Chem., 50(4), 1295-1303. 2011
[http://dx.doi.org/10.1021/ic102228u] [PMID: 21250638]
[9]
Sheikh, S.; Sturzu, A.; Kalbacher, H.; Nagele, T.; Weidenmairer, C.; Horger, M. A Novel Fluorescence-Labeled curcumin conjugate: synthesis, evaluation and imaging on human cell lines. Curr. Pharm. Des., 24(16), 1821-1826. 2018
[http://dx.doi.org/10.2174/1381612824666180406103317] [PMID: 29623828]
[10]
Sturzu, A.; Sheikh, S.; Echner, H.; Nägele, T.; Deeg, M.; Amin, B. Rhodamine-marked bombesin: a novel means for prostate cancer fluorescence imaging. Invest. New Drugs, 32(1), 37-46. 2014
[http://dx.doi.org/10.1007/s10637-013-9975-2] [PMID: 23728918]
[11]
Kohl, B.; Rothenberg, I.; Ali, S.A.; Alam, M.; Seebohm, G.; Kalbacher, H. Solid phase synthesis, NMR structure determination of α-KTx3.8, its in silico docking to Kv1.x potassium channels, and electrophysiological analysis provide insights into toxin-channel selectivity. Toxicon, 101, 70-78. 2015
[http://dx.doi.org/10.1016/j.toxicon.2015.04.018] [PMID: 25953725]
[12]
Sheikh, S.; Sturzu, A.; Kalbacher, H.; Klose, U.; Nagele, T.; Amin, B.; Deeg, M. Ramoplanin imaging conjugates--synthesis and evaluation. Med. Chem., 10(1), 18-26. 2014
[http://dx.doi.org/10.2174/157340641001131226121133] [PMID: 23646874]
[13]
Sheikh, S.; Sturzu, A.; Kalbacher, H.; Nagele, T.; Weidenmaier, C.; Horger, M. Fluorescein-labeled bacitracin and daptomycin conjugates: synthesis, fluorescence imaging and evaluation. Med. Chem., 2016, 13(1), 57-64.
[http://dx.doi.org/10.2174/1573406412666160330113420] [PMID: 27026529]
[14]
Sheikh, S.; Sturzu, A.; Klose, U.; Echner, H.; Deeg, M.; Nägele, T. Evaluating the diagnostic and chemotherapeutic potential of vancomycin-derived imaging conjugates. Med. Chem., 8(6), 1163-1170. 2012
[PMID: 22741805]
[15]
Sheikh, S.; Sturzu, A.; Kalbacher, H.; Nagele, T.; Weidenmaier, C.; Horger, M. A novel fluorescence-labeled curcumin conjugate: synthesis, evaluation and imaging on human cell lines. Curr. Pharm. Des., 24(16), 1821-1826. 2018
[http://dx.doi.org/10.2174/1381612824666180406103317] [PMID: 29623828]
[16]
Sheikh, S.; Sturzu, A.; Kalbacher, H.; Nagele, T.; Weidenmaier, C.; Horger, M. Fluorescence imaging of human cells with a novel conjugate of the antifungal nystatin. Med. Chem., 10(4), 348-354. 2014
[http://dx.doi.org/10.2174/15734064113099990028] [PMID: 24725140]
[17]
Sturchler-Pierrat, C.; Abramowski, D.; Duke, M.; Wiederhold, K.H.; Mistl, C.; Rothacher, S. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA, 94(24), 13287-13292. 1997
[http://dx.doi.org/10.1073/pnas.94.24.13287] [PMID: 9371838]
[18]
Duval, R.; Duplais, C. Fluorescent natural products as probes and tracers in biology. Nat. Prod. Rep., 34(2), 161-193. 2017
[http://dx.doi.org/10.1039/C6NP00111D] [PMID: 28125109]
[19]
Frid, P.; Anisimov, S.V.; Popovic, N. Congo red and protein aggregation in neurodegenerative diseases. Brain Res. Brain Res. Rev., 53(1), 135-160. 2007
[http://dx.doi.org/10.1016/j.brainresrev.2006.08.001] [PMID: 16959325]
[20]
Porat, Y.; Abramowitz, A.; Gazit, E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem. Biol. Drug Des., 67(1), 27-37. 2006
[http://dx.doi.org/10.1111/j.1747-0285.2005.00318.x] [PMID: 16492146]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy