1,3,5-Triazine Nitrogen Mustards with Different Peptide Group as Innovative Candidates for AChE and BACE1 Inhibitors

Maliszewski, Dawid; Wróbel, Agnieszka; Kolesińska, Beata; Frączyk, Justyna; Drozdowska, Danuta

doi:10.3390/molecules26133942

Cited by 14 publications

(15 citation statements)

References 37 publications

(42 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trolox-equivalent antioxidant capacity (TEAC) in mg TE/g sesame (ER) was used to express the radical scavenging activities. The enzymatic inhibition of acetylcholinesterase (AChE) and butylcholinesterase (BChE) was evaluated in a microplate using a spectrophotometric method with an acetylcholinesterase inhibitor screening kit (Sigma, MA, USA) [24] 2.5. Neuroprotective Effect in Amyloid-β Induced SH-SY5Y Cells of Lignan-Rich Sesame Cultivars Human neuroblastoma SH-SY5Y cells were obtained from the Korean Cell Line Bank (Seoul, Korea).…”

Section: Antioxidant and Cholinesterase Inhibitory Activities Of Diff...mentioning

confidence: 99%

Lignan-Rich Sesame (Sesamum indicum L.) Cultivar Exhibits In Vitro Anti-Cholinesterase Activity, Anti-Neurotoxicity in Amyloid-β Induced SH-SY5Y Cells, and Produces an In Vivo Nootropic Effect in Scopolamine-Induced Memory Impaired Mice

Kim

Lee

et al. 2023

Antioxidants

View full text Add to dashboard Cite

Alzheimer’s disease, a major cause of dementia, is characterized by impaired cholinergic function, increased oxidative stress, and amyloid cascade induction. Sesame lignans have attracted considerable attention owing to their beneficial effects on brain health. This study investigated the neuroprotective potential of lignan-rich sesame cultivars. Among the 10 sesame varieties studied, Milyang 74 (M74) extracts exhibited the highest total lignan content (17.71 mg/g) and in vitro acetylcholinesterase (AChE) inhibitory activity (66.17%, 0.4 mg/mL). M74 extracts were the most effective in improving cell viability and inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) generation in amyloid-β25-35 fragment-treated SH-SY5Y cells. Thus, M74 was used to evaluate the nootropic effects of sesame extracts and oil on scopolamine (2 mg/kg)-induced memory impairment in mice compared to the control cultivar (Goenback). Pretreatment with the M74 extract (250 and 500 mg/kg) and oil (1 and 2 mL/kg) effectively improved memory disorder in mice (demonstrated by the passive avoidance test), inhibited AChE, and enhanced acetylcholine (Ach) levels. Moreover, immunohistochemistry and Western blot results showed that the M74 extract and oil reversed the scopolamine-induced increase in APP, BACE-1, and presenilin expression levels in the amyloid cascade and decreased BDNF and NGF expression levels in neuronal regeneration.

show abstract

Section: Antioxidant and Cholinesterase Inhibitory Activities Of Diff...mentioning

confidence: 99%

Lignan-Rich Sesame (Sesamum indicum L.) Cultivar Exhibits In Vitro Anti-Cholinesterase Activity, Anti-Neurotoxicity in Amyloid-β Induced SH-SY5Y Cells, and Produces an In Vivo Nootropic Effect in Scopolamine-Induced Memory Impaired Mice

Kim

Lee

et al. 2023

Antioxidants

View full text Add to dashboard Cite

show abstract

“…Nitrogen mustards are important alkylating anticancer drugs, which have been used for a variety of solid neoplasms treatment,[ 16 ] especially in lung and breast cancers. [ 17 18 ] Over the past decades, a good deal of modifications have been made in the area of nitrogen mustard agent to improve its therapeutic effect due to its high reactivity and peripheral cytotoxicity. However, little research about the integration of luminophore into the nitrogen mustard-containing structure for imaging as auxiliary functions of therapeutic effect was reported.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of nitrogen mustard-based fluorophores for cell imaging and cytotoxicity studies

Liang¹,

Liang²,

Li³

et al. 2023

Journal of Advanced Pharmaceutical Technology &Amp; Research

View full text Add to dashboard Cite

Nitrogen mustards are important alkylating anticancer drugs used for neoplasms treatment. However, little research about the integration of luminophore into nitrogen mustard-based compounds for both imaging and therapeutic application was reported. In this study, we report a series of novel nitrogen mustard-containing 1-furyl-2-en-1-one and 1-thienyl-2-en-1-one derivatives as intramolecular charge transfer-based luminophore for research in both imaging subcellular localization and antiproliferation toward lung cancer cells. The target products were prepared by Knoevenagel condensation and characterized by nuclear magnetic resonance and high-resolution mass spectrometer. The absorption and fluorescence studies were carried out by ultraviolet-visible and fluorescence spectrophotometers, respectively. Cell morphology was observed under an inverted microscope. Cytotoxicity test was detected by MTT assay. Cellular localization was observed by a confocal laser scanning microscope. Colony formation ability was carried out by colony formation assay. Cell migration ability was detected by transwell migration assay. Differences between the two groups were analyzed by two-tailed Student's t-test. The difference with P < 0.05 (*) was considered statistically significant. The compounds were synthesized in high yield. The λmax and Stokes shift of these compounds reach up to 567 and 150 nm, respectively. These compounds exhibited good antiproliferative activity against lung cancer cells, with compound 3h exhibiting the best IC50 of 13.1 ± 2.7 μM. Furthermore, the selected compound 3h is located preferentially in lysosomes and a small amount in nuclei, effectively inhibiting cell colony formation and migration abilities toward A549 cells. These findings suggested that nitrogen mustard-based fluorophores might be a potential effective chemotherapeutic agent in lung cancer therapy.

show abstract

“…37 1,3,5-Triazine nitrogen mustards inhibit β-secretase (BACE1) enzyme, which is another key enzyme in the pathogenesis of AD, in addition to inhibiting cholinesterase. 40 3-Hydrazynyl 1,2,4-triazine derivatives 39 and 1,2,4-triazine derivatives with an indole moiety 43 also display BACE1 inhibitory potential. 1,3,5-Triazine derivatives, 42 benzotriazinone, and triazafluoranthenone 41 have been found to inhibit Aβ fibril formation and AChE activity.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In the search for potential small molecule inhibitors of these deleterious misfolded proteins, triazine, one of the privileged nitrogen-containing heterocycles, has drawn attention. This tridentate linker has been widely explored for the discovery and development of antifungal, anticancer, antimicrobial, and antiviral agents. − The application range of triazine-based compounds has been extended to neurodegenerative diseases, and some of these new compounds showed multitarget properties of anti-AD − or anti-PD agents . For example, cyanopyridine–triazine hybrids have been shown to disaggregate Aβ peptide as well as to inhibit cholinesterases including acetylcholinesterase (AChE), the latter of which comprises the target of several FDA-approved treatments for AD .…”

Section: Introductionmentioning

confidence: 99%

“…For example, cyanopyridine–triazine hybrids have been shown to disaggregate Aβ peptide as well as to inhibit cholinesterases including acetylcholinesterase (AChE), the latter of which comprises the target of several FDA-approved treatments for AD . 1,3,5-Triazine nitrogen mustards inhibit β-secretase (BACE1) enzyme, which is another key enzyme in the pathogenesis of AD, in addition to inhibiting cholinesterase . 3-Hydrazynyl 1,2,4-triazine derivatives and 1,2,4-triazine derivatives with an indole moiety also display BACE1 inhibitory potential.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of N- and O-Linked Indole Triazines for a Dual Effect on α-Synuclein and Tau Aggregation

Ramirez,

Ganegamage,

Min

et al. 2023

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder underlying dementia in the geriatric population. AD manifests by two pathological hallmarks: extracellular amyloid-β (Aβ) peptide-containing senile plaques and intraneuronal neurofibrillary tangles comprised of aggregated hyperphosphorylated tau protein (p-tau). However, more than half of AD cases also display the presence of aggregated α-synuclein (α-syn)-containing Lewy bodies. Conversely, Lewy bodies disorders have been reported to have concomitant Aβ plaques and neurofibrillary tangles. Our drug discovery program focuses on the synthesis of multitarget-directed ligands to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to slow the progression of AD and related dementias. To this end, we synthesized 11 compounds with a triazine-linker and evaluated their effectiveness in reducing α-syn, tau isoform 2N4R, and p-tau isoform 1N4R aggregation. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), and M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. We also performed disaggregation assays with isolated Aβ-plaques from human AD brains. Our results demonstrated that compound 10 was effective in reducing both oligomerization and fibril formation of α-syn and tau isoform 2N4R in a dose-dependent manner via ThT and PICUP assays. Compound 10 was also effective at reducing the formation of recombinant α-syn, tau 2N4R, and p-tau 1N4R fibrils by TEM. Compound 10 reduced the development of α-syn inclusions in M17D neuroblastoma cells and stopped the seeding of tau P301S using biosensor cells. Disaggregation experiments showed smaller Aβ-plaques and less paired helical filaments with compound 10. Compound 10 may provide molecular scaffolds for further optimization and preclinical studies for neurodegenerative proteinopathies.

show abstract

1,3,5-Triazine Nitrogen Mustards with Different Peptide Group as Innovative Candidates for AChE and BACE1 Inhibitors

Cited by 14 publications

References 37 publications

Lignan-Rich Sesame (Sesamum indicum L.) Cultivar Exhibits In Vitro Anti-Cholinesterase Activity, Anti-Neurotoxicity in Amyloid-β Induced SH-SY5Y Cells, and Produces an In Vivo Nootropic Effect in Scopolamine-Induced Memory Impaired Mice

Lignan-Rich Sesame (Sesamum indicum L.) Cultivar Exhibits In Vitro Anti-Cholinesterase Activity, Anti-Neurotoxicity in Amyloid-β Induced SH-SY5Y Cells, and Produces an In Vivo Nootropic Effect in Scopolamine-Induced Memory Impaired Mice

Synthesis of nitrogen mustard-based fluorophores for cell imaging and cytotoxicity studies

Evaluation of N- and O-Linked Indole Triazines for a Dual Effect on α-Synuclein and Tau Aggregation

Contact Info

Product

Resources

About