Table 2.
Oxidative stress properties of curcumin analogues, derivatives, and hybrids in AD.
| Ref. | Structure or Functional Groups | Antioxidant Activity | Metal Accumulation | Mitochondrial Dysfunction/Apoptosis | Techniques | In Vitro/In Vivo/Ex Vivo/In Silico | Blood–BrainBarrier (BBB) Permeation |
|---|---|---|---|---|---|---|---|
| [82] | Mono-ketone moiety Phenolic OH |
(i) inhibit ROS accumulation (ii) inhibit oxidative stress via Keap1/Nrf2/HO-1 signaling pathways |
- | (i) increase Bcl-2 expression level (ii) decrease the level of Bax and Cyt-c |
ROS production assay (DCFH-DA probe) | In vitro (PC12 cells) |
NI |
| [6] | 1,7-Bis(3,4-dihydroxyphenyl)-1,6-heptadiene-3,5-dione | reduce intracellular ROS | - | (i) increase the ratio of Bcl-XL/Bax protein level, cytochrome c protein expression (ii) cleave caspase-9 and caspase-3 protein expression |
(i) determination of intracellular ROS by DCF assay (ii) Cell apoptosis analysis |
In vitro (SK-N-SH cells) |
NI |
| [63] | 4-Hydroxyl group | significant decrease in ROS generation and a significant increase in GSH level | - | - | (i) ROS production assay (DCFH-DA probe) (ii) determination of glutathione (GSH) |
In vitro (SK-N-SH cells) |
pass |
| [55] | Tetrahydro-curcumin (THC) | increases in the level of reactiveoxygen species | - | (i) decrease in mitochondrial membrane potential, (ii) caspase activation |
(i) ROS production assay (DCFH-DA probe) (ii) mitochondrial membrane potential assay (iii) caspase-3 activity assay |
In vitro (rat primary hippocampal and human neuron cultures) |
NI |
| [20] | Demethylcurcumin | IncreasesGSH and reduceds reactive oxygen species (ROS) | - | - | (i) ROS production assay (DCFH-DA probe) (ii) glutathione (GSH) assay |
In vitro (HT4 neuronal cells) |
pass |
| [60] | Phenol groups | effect on Aβ-induced ROS production in vitro and in vivo | - | - | (i) ROS production assay (DCFH-DA probe) (ii) lipid peroxidation inhibition |
In vitro (SH-SY5Y cells) In vivo |
NI |
| [8] | Curcumin congeners with different polyamine motifs | decrease of ROS levels | - | an efficientintracellular uptake and mitochondria targeting | (i) ROS production assay (DCFH-DA probe) (ii) heme oxygenase-1 (HO-1) induction |
In vitro (SH-SY5Y, hippocampal neuronal HT22 cell lines, T67 glioma cells) |
NI |
| [42] | (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N′-(3-methoxy-benzylidene)acetohydrazide | - | - | - | (ii) heme oxygenase-1 (HO-1) induction | In vivo (APP/PS1 transgenic mice) |
pass |
| [18] | Vanillin moieties 4-Hydroxy,3-methoxy group |
(i) reduction of H2O2-induced intracellular ROS production (ii) activation of antioxidant Nrf2 signaling |
- | - | DCFH-fluorescence intensity in H2O2-treated cells | In vitro (SH-SY5Y cells) |
NI |
| [9] | The styryl function and steric or electronic factors through the large aromatic structure A dimethylamino groupon benzene ring |
reduction of oxidative stress | selectively chelating metal ions such as copper and iron | - | (i) ORAC (oxygen radical absorbance capacity) (ii) ORAC-FL |
In vitro | NI |
| [11] | The styryl function and steric or electronic factors through the introduction of the piperazine groups | ability to counteract the formation of ROS | chelate metals such as iron and copper | - | (i) ROS production assay (DCFH-DA probe) (ii) ORAC |
In vitro (SH-SY5Y cells) |
NI |
| [16] | Phenolic hydroxy groups | - | - | - | DPPH | In vitro | pass |
| [27,40] | Hydroxyl substituent on the aromatic ring Keto-enolic group A phenolic group combined with methoxyl moiety in ortho position |
complexes display possible superoxide dismutase (SOD)-like activity | ability to bind Cu(II) ion | - | (i) DPPH (ii) xanthine/xanthine oxidase assay |
In vitro | NI |
| [87] | Phenolic OH group CH2 group of the β-diketone moiety Pyrazole ring andmethoxy groups |
enhancing levels of: (i) GSH (mg/g brain tissue) (ii) paraxosnase (kl/mg protein) |
- | decrease in brain 8-OHG level, caspase-3 level, and brain p53 level | - | In vitro In vivo (female albino rats) |
pass |
| [22] | 4,4′-((1E,1′E)-(1-phenyl-1H- pyrazole-3,5-diyl)bis(ethene-2,1-diyl))bis(2-methoxyphenol) |
(i) O2•- scavenging activity was much lower than that of curcumin (ii) OH• scavenging activity was similar to that of curcumin |
- | - | (i) ORAC (O2•-) (ii) HORAC (OH•) |
In vitro | pass |
| [39] | Incorporates a C5-monoketone spacer moiety and phenolic rings bearing hydroxy groups at positions 2,3,2′,5′ | - | - | - | DPPH | In vitro | |
| [23] | (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxyphenyl)hepta-1,4,6-trien-3-one | - | - | - | (i) DPPH (ii) FRAP assay |
In vitro | NI |
| [43,88] | (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N′-(3-methoxy-benzylidene)acetohydrazide | - | - | exhibits favorable bindingat the allosteric site of mATP synthase with considerable electrostatic energy contributionsfrom Gln215, Gly217, Thr219, Asp312, Asp313, Glu371, and Arg406 | - | (i)homology modeling, validation, and active site identification (ii) molecular dynamics (MD) simulation (ii) docking |
NI |
| [89] | 7-(4-Hydroxy-3-methoxyphenyl)-1-phenyl-4E-hepten-3-one | - | - | (i)protects cortical neurons fromOGD/R-induced autophagic apoptosis (ii) suppresses OGD/R-induced autophagyand apoptosis in mTOR-dependent manner |
OGD/Rinducedcell apoptosis was detected using the Annexin VFITC/PI (propidium iodide) Apoptosis detection kit | In vivo | pass |
| [81] | A 7-carbon dienone spacer A 5-carbon enone spacer with and without a ring A 3-carbon enone spacer |
activation of antioxidant Nrf2 signaling | - | - | DPPH radical scavenger assay | In vitro (Nrf2-ARE reporter-HepG2 stable cell line) |
NI |
| [90] | Bivalent compounds with varied spacer length and cell membrane anchor moiety | - | - | (i) can reverse the increased mitochondrial membrane potential (ii) can abolish the cytosolic Ca2+increase upon TC removal |
(i) MC65 apoptosis assay (ii) MC65 mitochondrial membrane potential assay (iii) SH-SY5Y mitochondrial membrane potential assay |
In vitro (SH-SY5Y andMC65 cells) |
NI |
| [29] | Gd(III) (diethylenetriamine-penta-acetate)-linked-2-(4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxy-phenyl)-3-oxohepta-1,4,6-trien-1-yl)-2-methoxy-phenoxy)-N-(2-(3-(ptolyl)thioureido)ethyl)acetamide | - | metal binding properties | - | trolox equivalent antioxidant capacity (TEAC) assay | In vitro (N2a cell line) |
NI |
| [91] | Tetrahydrocurcumin | - | - | tetrahydrocurcumin treatment suppressed neuronal apoptosis in injured brains | - | In vivo | pass |
| [62] | Cholesterylamine spacer (length of 17 atoms) |
antioxidant activity | metal-chelating properties (Cu, Fe, and Zn) | - | ROS production assay (DCFH-DA probe) | In vitro (MC65 cells) |
NI |
| [92] | Bivalent compounds with varied spacer length and cell membrane anchor moiety | - | - | suppress the change of MMP, possibly via interaction with the mitochondrial complex I |
(i) MC65 mitochondrial membrane potential assay (ii) SH-SY5Y mitochondrial membrane potential assay |
In vitro (MC65 and SH-SY5Y cells) |
NI |
| [26] | (1E,4Z,6E)-1-(4-(benzyloxy)phenyl)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one (1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(p-tolyl)hepta-1,4,6-trien-3-one (1E,4Z,6E)-7-(4-(benzyloxy)phenyl)-5-hydroxy-1-(4-methoxyphenyl)hepta-1,4,6-trien-3-one |
ROS NQO1 induction |
- | - | (i) ROS production assay (DCFH-DA probe) (ii) assay for NQO1 induction |
In vitro (T67 cells) |
pass |
| [65,66] | 5-(4-Hydroxyphenyl)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-3-oxopentanamide | possible function against ROS accumulation | - | increased the expression level of complexes I, II, and IV of the mitochondria electron transport chain in the brain tissue of APP/PS1 mice | (i) ROS production assay (DCFH-DA probe) (ii) hydrogen peroxide toxicity |
In vitro (MC65 cells, HT22 cells) In vivo |
pass |
| [24] | 4-(1-Benzylpiperidin-4-yl)-1-(3-hydroxy-4-methoxyphenyl)butane-1,3-dione | antioxidant activity | metal-chelating properties | - | ORAC-FL | In vitro (PC12 cells) |
pass |
| [68] | Methoxy and hydroxyl groups | antioxidant activity | - | - | ORAC | In vitro | pass |
| [69,93] | (E)-(1-benzylpiperidin-4-yl)methyl 3-(4-hydroxy-3-methoxyphenyl)acrylate | (i) decreases ROS (ii) increases GSH levels |
- | - | (i) ROS production assay (DCFH-DA probe) (ii) glutathione (GSH) assay |
In vitro (human neuronal cells) In vivo |
pass |
| [58] | 2-Methoxy-4-(piperidin-1-ylmethyl)phenyl dimethylcarbamate | antioxidant activity | metal-chelating properties | - | ABTS assay | In vitro | NI |
| [94] | Phenolic hydroxyl group | antioxidant activity | metal-chelating properties | - | ORAC | In vitro | NI |
NI, no information is available.