Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones

Elzahhar, Perihan A.; Alaaeddine, Rana; Nassra, Rasha A.; Ismail, Azza; Labib, Hala F.; Temraz, Mohamed G.; Belal, Ahmed S.F.; El‐Yazbi, Ahmed F.

doi:10.1080/14756366.2021.1887169

Cited by 9 publications

(4 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The docking studies were conducted using MOE 2019.0102 software (Chemical Computing Group, Montreal, Canada) using the crystal structure of human MDM2 protein active site (PDB 3LBL), as previously described . Hydrogen atoms were added to the database of test compounds, partial charges were computed, and energy minimization was supported by Force Field MMFF94x.…”

Section: Methodsmentioning

confidence: 99%

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

et al. 2023

Self Cite

View full text Add to dashboard Cite

Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53–MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.

show abstract

Section: Methodsmentioning

confidence: 99%

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…The cytotoxic effect of different Punica granatum L. extracts were in vitro measured using the MTT method as described previously and according to the manufacturer's protocol 20 . Details are found under Supporting Information, Methods S1.…”

Section: Methodsmentioning

confidence: 99%

Comparative metabolomics reveal intraspecies variability in bioactive compounds of different cultivars of pomegranate fruit (Punica granatum L.) and their waste by‐products

et al. 2022

View full text Add to dashboard Cite

BACKGROUND The different parts of pomegranate fruit are considered a powerful mixture of bioactive compounds yet the peels and pulps of the fruits are usually discarded and considered as industrial waste. In this work, ultra‐performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC‐QqQ‐MS) was utilized for metabolomics analysis of different parts (peel, pulp, seed and juice) of pomegranate fruit cultivars to verify possible variations among the fruits and their waste products as potential sources of functional constituents. RESULTS Orthogonal projection to latent structure‐discriminant analysis (OPLS‐DA) coefficient‐plot showed enrichment of phenolic compounds such as punicalagin and ellagic acid derivatives in pulp samples while seeds class was enriched in phlorizin, catechin and quercetin, juice class showed abundance of naringenin and pelargonidin‐3‐pentoside while peels were enriched in anthocyanins and flavonoids including cyanidin diglycoside, quercetin and luteolin glycosides. Although the juice samples of almost all tested cultivars showed remarkable cytotoxic activity, the pulp samples, particularly the Manfalouti cultivar, exhibited the most potent [half maximal inhibitory concentration (IC50) = 2.367 ± 0.14 μg/mL in MCF‐7, IC50 = 3.854 ± 0.23 μg/mL in Hep‐G2 cell lines]. OPLS models were constructed for determination of cytotoxicity‐associated metabolites among where the coefficients plots revealed tannins; granatin A, ellagic acid derivatives, punicalagin α and β, in addition to anthocyanins and phenolic compounds; cyanidin diglycoside, quercetin, phlorizin, 3‐O‐caffeoylquinic acid, naringenin and liquiritin were more pertinent with cytotoxicity of the different parts of pomegranate fruit. CONCLUSION The results obtained allow for the full utilization of the resources of pomegranate fruit and its industrial waste as sources of bioactive compounds. © 2022 Society of Chemical Industry.

show abstract

“…On the other hand, several drug lead generation programs addressed the need for drugs targeting low-grade adipose inflammation using innovative chemistry to render efficacious molecular tools. The use of click chemistry enabled the design of simple synthetic schemes generating multi-target directed ligands (MTDLs) via the fusion of disparate pharmacophores into the same molecular scaffold in a manner that might not have been achieved as easily otherwise (Alaaeddine et al, 2021;Elzahhar et al, 2019;Elzahhar et al, 2021;Moussa et al, 2018). This approach has proven useful in developing compounds with superior activity against acute and chronic inflammatory models, macrophage differentiation and pro-inflammatory polarization, neuroinflammation, and adipose inflammation.…”

Section: Downloaded Frommentioning

confidence: 99%

Thermogenic Modulation of Adipose Depots: A Perspective on Possible Therapeutic Intervention with Early Cardiorenal Complications of Metabolic Impairment

El-Yazbi,

Elrewiny,

Habib

et al. 2023

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Cardiovascular complications of diabetes and obesity remain a major cause for morbidity and mortality worldwide. Despite significant advances in the pharmacotherapy of metabolic disease, the available approaches do not prevent or slow the progression of complications. Moreover, a majority of patients present with significant vascular involvement at early stages of dysfunction prior to overt metabolic changes. The lack of disease-modifying therapies affects millions of patients globally, causing a massive economic burden due to these complications. Significantly, adipose tissue inflammation was implicated in the pathogenesis of metabolic syndrome, diabetes, and obesity. Specifically, perivascular (PVAT) and perirenal adipose tissue (PRAT) depots influence cardiovascular and renal structure and function. Accumulating evidence implicates localized PVAT/PRAT inflammation as the earliest response to to metabolic impairment leading to cardiorenal dysfunction. Increased mitochondrial uncoupling protein-1 (UCP1) expression and function leads to PVAT/PRAT hypoxia, inflammation, as well as vascular, cardiac, and renal dysfunction. As UCP1 function remains an undruggable target so far, modulation of the augmented UCP1-mediated PVAT/PRAT thermogenesis constitutes a lucrative target for drug development to mitigate early cardiorenal involvement. This can be achieved either by subtle targeted reduction in UCP-1 expression using innovative proteolysis activating chimeric molecules (PROTACs) or by supplementation with cyclocreatine phosphate, which augments the mitochondrial futile creatine cycling and thus, decreases UCP1 activity, enhances the efficiency of oxygen use and reduces hypoxia. Once developed, these molecules will be first-in-class therapeutic tools to directly interfere with and reverse the earliest pathology underlying cardiac, vascular, and renal dysfunction accompanying the early metabolic deterioration.

show abstract

Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones

Cited by 9 publications

References 67 publications

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

Comparative metabolomics reveal intraspecies variability in bioactive compounds of different cultivars of pomegranate fruit (Punica granatum L.) and their waste by‐products

Thermogenic Modulation of Adipose Depots: A Perspective on Possible Therapeutic Intervention with Early Cardiorenal Complications of Metabolic Impairment

Contact Info

Product

Resources

About