Fluorinated Molecules and Nanotechnology: Future ‘Avengers’ against the Alzheimer’s Disease?
Abstract
:1. Introduction
2. The Role of Fluorine in the Development of Therapeutic Drugs
2.1. The Role of Fluorine-Containing Compounds in the Modulation of Amyloid-Beta Peptide
2.2. The Role of Fluorine-Containing Compounds in the Modulation of the Secretases
3. Nanoparticles Designed with Fluorine Molecules for the Treatment of Alzheimer’s Disease
4. Conclusion and Future Perspective
Author Contributions
Funding
Conflicts of Interest
Abbreviations
α | Alpha |
β | Beta |
Aβ | Amyloid-beta |
AD | Alzheimer’s disease |
AFM | Atomic force microscopy |
BACE | β-Site amyloid precursor protein cleaving enzyme |
BBB | Blood-brain barrier |
CD | Circular dichroism |
CNS | Central nervous system |
CSF | Cerebrospinal fluid |
DFT | Density functional theory |
EtOH | Ethanol |
FAD | Familial Alzheimer’s disease |
FTIR | Fourier-transform infrared spectroscopy |
HFIP | Hexafluoroisopropanl |
LTP | Long-term potentiation |
NBO | Natural bond orbital |
NMR | Nuclear magnetic resonance |
NPs | Nanoparticles |
Teflon | Polytetrafluoroethylene |
TEM | Transmission electron microscopy |
TFE | Trifluoroethanol |
Tfm | Trifluoromethylated |
THF | Tetrahydrofuran |
ThT | Thioflavin T |
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Compounds | Site of Action | Observed Effects | Models Used | Reference |
---|---|---|---|---|
Fluorinated alcohols (TFE and HFIP) | Aβ40 peptide | Induce conformational transition from β-sheet to α-helical structure | Stock solution of Aβ40 peptide | [51] |
LVfFFD-PEG and LVFfFD-PEG | Aβ42 peptide | Delay the formation of the Aβ aggregates | Stock solution of Aβ42 peptide | [56] |
(R)-α-trifluoromethylalanine | Delays the conformational transition for at least 96 h; Slows the kinetic depletion rate of Aβ monomers | Stock solution of Aβ42 peptide | [57] | |
5′-halogen substituted 3,3,3-trifluoromethyl-2-hydroxyl-(indol-3-yl)-propionic acid esters | Aβ40 peptide | Inhibits the fibrillogenesis; Disassemble preformed fibrils | Stock solution of Aβ40 peptide | [58,59,60] |
Cromolyn-based fluorinated derivative | Aβ40 and Aβ42 aggregates | Inhibits the Aβ oligomerization; Displays significant brain uptake and clearance activity | Stock solution of Aβ40 and Aβ42 peptideand WT mice | [62] |
Organofluorine inhibitor | Aβ40 peptide | Improve the cognitive impairment; Enhance the BBB permeability | Stock solution of Aβ40 peptide and mice | [63] |
SEN 1500 | Aβ42 peptide | Demonstrates anti-aggregating capability; Blocks the toxic effect in LTP | Stock solution of Aβ42 peptide, SH-SY5Y cells and 7PA2 CM cells | [65] |
8-fluoro-3,4-dihydro-2H benzo [1,4] oxazine inhibitor | Inhibits Aβ aggregation; Shows excellent neuroprotective profile | Stock solution of Aβ42 peptide, SH-SY5Y cells, hippocampal slices of male young rat (6–8 weeks old) | [65] | |
Fluorinated surface (Teflon) | Aβ40 peptide | Promotes α-helix reformation | Stock solution of Aβ40 peptide | [66] |
Compounds | Site of Action | Observed Effects | Model Used | Reference |
---|---|---|---|---|
Fluorinated ethanolamines | β-secretase (BACE1) | Inhibits BACE1 activity | Enzymatic assay (human BACE1), human neuroblastoma SKNBE2 cells | [72] |
LY-2886721 | Decreases the Aβ levels in CSF | Human. Terminated after phase 2 due to liver toxicity | [75] | |
Fluorinated LY-2886721 | Reduces the amyloid levels | HEK293 cells (Human BACE1)PDAPP young mice | [76] | |
1,3 oxazine-based BACE1 inhibitor (difluoroethyl substituted analogue) | Display good BACE1/2 selectivity; Reduce Aβ levels in CSF | HEK293 cells (Both human BACE1 and BACE2) male beagle dogs | [78] | |
Eisai’s BACE1 inhibitor [1,3] thiazine series Fluoro(methyl) analogues | Enhance the basicity and show selectivity over BACE2 | Human/Rat Aβ42; neuronal cultures of rat’s fetus brain | [80,81] | |
Organofluorine substituted BACE1 inhibitors | Improve the drug efficacy (non-P-gp substrates) | Neuroblastoma SH-SY5Y cells, human liver microsomes, ICR mice (7–9 weeks old) | [82] | |
Fluorinated oxazines analogues | Enhance potency and basicity; Reduce the Aβ levels at low doses | Enzymatic assays (BACE1 and BACE2), HEK293 cells, LLC-PK1 cells, female WT-mice | [88] |
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Dabur, M.; Loureiro, J.A.; Pereira, M.C. Fluorinated Molecules and Nanotechnology: Future ‘Avengers’ against the Alzheimer’s Disease? Int. J. Mol. Sci. 2020, 21, 2989. https://doi.org/10.3390/ijms21082989
Dabur M, Loureiro JA, Pereira MC. Fluorinated Molecules and Nanotechnology: Future ‘Avengers’ against the Alzheimer’s Disease? International Journal of Molecular Sciences. 2020; 21(8):2989. https://doi.org/10.3390/ijms21082989
Chicago/Turabian StyleDabur, Meghna, Joana A. Loureiro, and Maria Carmo Pereira. 2020. "Fluorinated Molecules and Nanotechnology: Future ‘Avengers’ against the Alzheimer’s Disease?" International Journal of Molecular Sciences 21, no. 8: 2989. https://doi.org/10.3390/ijms21082989