In the present paper, on the basis of molecular hybridization, a series of 4,6-dihydrazone pyrimidine derivatives containing the pyridine moiety were synthesized, structurally characterized, and ...evaluated in vitro for their antitumor activity. According to the results, all the tested compounds demonstrated broad-spectrum antitumor activity against selected tumor cell lines (MCF-7, BGC-823, A549, and BEL-7402) and no obvious toxicity toward normal cells HL-7702. In particular, compounds
and
were found to be the most promising antitumor agents among the tested compounds against BGC-823 cells (IC
= 9.00 μM and 7.89 μM) and BEL-7402 cells (IC
= 6.70 μM and 7.66 μM), respectively. Compounds
and
exhibited higher potency against BGC-823 and BEL-7402 than the positive control 5-FU (IC
= 15.18 μM and 15.81 μM). Further mechanism investigations demonstrated that compounds
and
could significantly increase the level of cellular ROS and induce early apoptosis of BGC-823 cells in a dose-dependent manner. Moreover, the DNA binding results from UV/Vis, CD spectroscopy, and molecular docking studies indicated that
and
bind with DNA via groove binding and partial intercalation. These results demonstrated that
and
may serve as novel lead compounds for the discovery of more dihydrazone pyrimidine derivatives with improved antitumor potency and selectivity.
The impairment of amyloid-β (Aβ) clearance in the brain plays a causative role in Alzheimer's disease (AD). Polarity distribution of aquaporin-4 (AQP4) is important to remove Aβ from brain. AQP4 ...polarity can be influenced by the ratio of two AQP4 isoforms M1 and M23 (AQP4-M1/M23), however, it is unknown whether the ratio of AQP4-M1/M23 changes in AD. Histone deacetylase 3 has been reported to be significantly increased in AD brain. Moreover, evidence indicated that microRNA-130a (miR-130a) possibly mediates the regulation of histone deacetylase 3 on AQP4-M1/M23 ratio by repressing the transcriptional activity of AQP4-M1 in AD. This study aimed to investigate whether intermittent fasting (IF), increasing the level of an endogenous histone deacetylases inhibitor β-hydroxybutyrate, restores AQP4 polarity via miR-130a mediated reduction of AQP4-M1/M23 ratio in protection against AD. The results showed that IF ameliorated cognitive dysfunction, prevented brain from Aβ deposition, and restored the AQP4 polarity in a mouse model of AD (APP/PS1 double-transgenic mice). Additionally, IF down-regulated the expression of AQP4-M1 and histone deacetylase 3, reduced AQP4-M1/M23 ratio, and increased miR-130a expression in the cerebral cortex of APP/PS1 mice.
, β-hydroxybutyrate was found to down-regulate the expression of AQP4-M1 and histone deacetylase 3, reduce AQP4-M1/M23 ratio, and increase AQP4-M23 and miR-130a expression in 2 μM Aβ-treated U251 cells. Interestingly, on the contrary to the result observed in 2 μM Aβ-treated cells, AQP4 expression was obviously decreased in cells exposed to 10 μM Aβ. miR-130a mimic decreased the expression of AQP4-M1 and the ratio of AQP4-M1/M23, as well as silencing histone deacetylase 3 caused the up-regulation of AQP4 and miR-130a, and the reduction of AQP4-M1/M23 ratio in U251 cells. In conclusion, IF exhibits beneficial effects against AD. The mechanism may be associated with recovery of AQP4 polarity, resulting from the reduction of AQP4-M1/M23 ratio. Furthermore, β-hydroxybutyrate may partly mediate the effect of IF on the reduction of AQP4-M1/M23 ratio in AD, in which miR-130a and histone deacetylase 3 may be implicated.
Intermittent fasting has been demonstrated to protect against Alzheimer's disease (AD), however, the mechanism is unclear. Histone acetylation and lipoprotein lipase (LPL) are involved in AD ...progression. Importantly, LPL has been documented to be regulated by histone deacetylases (HDACs) inhibitors (increase histone acetylation level) in adipocyte and mesenchymal stem cells, or by fasting in adipose and muscle tissues. In brain, however, whether histone acetylation or fasting regulates LPL expression is unknown. This study was designed to demonstrate intermittent fasting may protect against AD through increasing β-hydroxybutyrate, a HDACs inhibitor, to regulate LPL. We also investigated microRNA-29a expression associating with regulation of LPL and histone acetylation. The results showed LPL mRNA expression was increased and microRNA-29a expression was decreased in the cerebral cortex of AD model mice (APP/PS1), which were alleviated by intermittent fasting. No significant differences were found in the total expression of LPL protein (brain-derived and located in capillary endothelial cells from peripheral tissues) in the cerebral cortex of APP/PS1 mice. Further study indicated that LPL located in capillary endothelial cells was decreased in the cerebral cortex of APP/PS1 mice, which was alleviated by intermittent fasting. LPL and microRNA-29a expression were separately increased and down-regulated in 2 μM Aβ
-exposed SH-SY5Y cells, but respectively decreased and up-regulated in 10 μM Aβ
-exposed cells, which were all reversed by β-hydroxybutyrate. The increase of HDAC2/3 expression and the decrease of acetylated H3K9 and H4K12 levels were alleviated in APP/PS1 mice by intermittent fasting treatment, as well in 2 or 10 μM Aβ
-exposed cells by β-hydroxybutyrate treatment. These findings above suggested the results from APP/PS1 mice were consistent with those from cells treated with 2 μM Aβ
. Interestingly, LPL expression was reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression.
Five novel
tropos
(3
R
,4
R
)- and/or (3
S
,4
S
)-
N
-benzyltartarimide-derived biphenylphosphite ligands were synthesized and applied in the Cu-catalyzed asymmetric conjugate addition of diethylzinc ...to cyclic enones with up to 75%
e.e
. Compared with the reported ligand 1-
N
-benzylpyrrolidine-3,4-bis(
R
)-1,1’-binaphthyl-2,2’-diylphosphite-
L
-tartaric acid, the issue that
L
-(+)-tartaric acid backbone and (
R
)-binaphthyl showed strong matched/mismatched character was solved with these
tropos
ligands. It was found that the enantioselectivity was mainly controlled by the absolute configuration of
N
-benzyltartarimide backbone, and both enantiomers of the addition products can be obtained by simply changing the configuration of
N
-benzyltartarimide substituent.
•The Schiff bases 1–3 from 2-amino-4‑tert-butylphenol were synthesized and characterized by NMR,IR,HRMS and UV–vis.•The crystal structures of 1 and 3 were established by single crystal X-ray ...diffraction.•The DPPH radical scavenging rates of compounds 1 (92.62%) and 2 (91.05%) are comparable to that of Vitamin C (98.31%) at the concentration of 1.0 mg/mL.•The DFT theoretical results show that the ET-PT mechanism is reasonable and in line with the experimental well.
Schiff bases are chemical compounds formed from the condensation reaction of aldehydes or ketones with amines. In medicinal chemistry, these compounds have received widespread attention due to significant biological activities, including antioxidant, antibacterial, antifungal, antiviral, antitumor, and anti-inflammatory. Herein, three Schiff base compounds, namely 2-(3, 5-di‑tert‑butyl‑2-hydroxybenzylideneamino)-4‑tert-butylphenol (1), 2-(4-(diethylamino)-2-hydroxybenzylideneamino)-4‑tert-butylphenol (2) and (1E)-1-((5‑tert‑butyl‑2-hydroxyphenylamino)methylene)naphthalen-2(1H)-one (3) were synthesized and characterized by NMR,IR,HRMS and UV–vis. Moreover, the structures of compounds 1 and 3 were determined by single crystal X-ray diffraction techniques. The theoretically simulated NMR, IR and the UV-visible absorption spectra have been compared with the experimental datas. Based on the absorbed UV spectra and TD-DFT calculations, assignment of the absorption bands are carried out. The antioxidant capacity of three butylphenol derivatives was evaluated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging experiments using Vitamin C as a standard drug. The scavenging rates of compounds 1 (92.62%) and 2 (91.05%) were comparable to that of Vitamin C (98.31%) at the concentration of 1.0 mg/mL. In order to investigate the DPPH free radical scavenging mechanism, a theoretical study based on density functional theory (DFT) was performed. The results show that ET-PT mechanism is favored which is in agreement with the experimental results.
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•The heterocyclic phenolic hydrazone L1-L4 were synthesized and characterized by NMR, HRMS, IR and UV–vis.•Compound L3 demonstrated higher activity against three cancer cell lines (BGC-823, MCF-7 and ...A549) than the anticancer 5-FU using MTT assay.•Compound L3 is more effective in scavenging free radicals than the antioxidant BHT by DPPH and ABTS assays.•DFT, molecular docking and drug-likeness studies were also investigated for compounds L1-L4.
In this research, the anticancer and antioxidant activities of a novel class of heterocyclic phenolic hydrazone derivatives were investigated. The structure determination of the synthesized compounds was carried out through nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry and infrared spectroscopy. The antiproliferative activities of the synthesized compounds were examined against three cancer cell lines (BGC-823, MCF-7 and A549). Specifically, L3 showed better antiproliferative activity against these three cancer cell lines than standard 5-FU, but had no toxic effect on normal human liver cell line (HL-7702). In addition, DPPH and ABTS methods were used to evaluate the antioxidant activity of the synthesized compounds. Compound L3 was more effective in scavenging free radicals than the antioxidant BHT. The results of the structure-activity relationship study revealed that the rules governing anticancer and antioxidant activities of these compounds were similar. Specifically, the introduction of hydroxyl groups, quinoline and benzothiazole ring usually had a positive effect on activities, while the electron-withdrawing group (F) at the C5-position of the pyrimidine ring linked to imine bond were not favorable. The DFT computations were carried out using the B3LYP functional with def2-SVP basis set and calculation was executed via Gaussian 16 software. Frontier molecular orbital (FMO) analysis showed that high chemical potential highlighted the stronger binding affinity of compounds L3 and L4, indicating stronger potential interactions with amino acids. The electrophilic and nucleophilic reaction sites of these molecules were identified using molecular electrostatic potential (MEP). In addition, molecular docking studies were conducted to gain a deeper understanding of the interactions between 2CDU and 4AGM proteins and these compounds. Compared with the reference drugs, the studied compound showed higher binding affinity. Furthermore, the bioavailabilities of the synthesized compound have been established by the study of drug-likeness. The high human intestinal absorption (HIA) value indicated that compound L3 exhibited excellent oral efficacy. The above results indicated that the synthesized heterocyclic phenolic hydrazone derivatives may be effective pharmaceutical compounds and could be used as anticancer and antioxidant agents.
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Abstract
C
24
H
19
N
3
O, monoclinic,
P
2
1
/
c
(no. 14),
a
= 10.4783(5) Å,
b
= 11.7171(5) Å,
c
= 14.9194(6) Å,
β
= 93.991(2)°,
Z
= 4,
V
= 1827.29(14) Å
3
,
R
gt
(
F
) = 0.0521,
wR
ref
(
F
2
...) = 0.1508, T = 150(2) K.
Scope
γ‐Aminobutyric acid (GABA) possesses extensive physiological functions and can be directly obtained from foods. GABA‐enriched functional foods have been developed and the commercial demands for ...GABA are increasing. GABA is widely recognized as a central nervous system inhibitory neurotransmitter and plays an important role in some diseases by binding to its receptors. However, some of the functions of GABA are not explained by neurotransmission or GABA receptor pathways. Therefore, this study investigates whether GABA has the potential to inhibit histone deacetylase (HDAC).
Methods and results
It is found that GABA inhibits HDAC1/2/3 expression and upregulates histone acetylation levels (Ace‐H3K9/Ace‐H4K12) in SH‐SY5Y cells (which express GABA receptors), 3T3‐L1 cells (which do not express GABA receptors), and the cerebral cortex in mice. Glutamate receptor 2 (GluR2) is a subunit of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptor and is implicated in the pathogenesis of some neurological diseases. It is also found that GABA increases GluR2 expression by inhibiting HDAC1/2 but not HDAC3.
Conclusion
A novel role for GABA is demonstrated in which it acts as an HDAC inhibitor. The present study expands the horizons for exploring the non‐neurotransmitter functions of GABA.
γ‐Aminobutyric acid inhibits histone deacetylase (HDAC)1/2/3 expression and upregulates histone acetylation levels (Ace‐H3K9/Ace‐H4K12) in SH‐SY5Y cells, 3T3‐L1 cells, and the cerebral cortex of mice. The results also show that GABA increases GluR2 expression by inhibiting HDAC1/2 but not HDAC3. The study reveals a novel role for GABA in which it acts as an HDAC inhibitor.
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