Beyond direct Nrf2 activation; reinvestigating 1,2,4-oxadiazole scaffold as a master key unlocking the antioxidant cellular machinery for cancer therapy

Ayoup, Mohammed Salah; Abu‐Serie, Marwa M.; Hamid, Hamida Abdel; Teleb, Mohamed

doi:10.1016/j.ejmech.2021.113475

Cited by 26 publications

(23 citation statements)

References 118 publications

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“…Cytotoxicity screening. The newly synthesized Passerini adducts 7a-k were preliminarily screened utilizing the microculture MTT assay 39 to evaluate their potential antiproliferative activities against normal human fibroblasts (Wi-38), colorectal (Caco-2) and hepatocellular (HepG-2) cancer cells compared to the standard chemotherapy 5-fluorouracil that promote caspase-dependent apoptosis in various cancers 40,41 (Table 1). Obviously, all derivatives were superior to 5-fluorouracil against the screened cell lines concerning potency and selectivity.…”

Section: Resultsmentioning

confidence: 99%

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Ayoup

Wahby

Hamid

et al. 2022

Sci Rep

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Selective elimination of tumors has always been the mainstay of oncology research. The on-going research underlying the cellular apoptotic mechanisms reveal caspases activation, especially the key effector caspase-3, as a personalized tumor-selective therapeutic strategy. Our continued research protocol has exploited new optimized Passerini α-acyloxy carboxamides as efficient apoptotic inducers via caspase-3/7 dependent mechanism with highly selective anticancer profiles. The adopted design rationale relied on excluding structural alerts of previous leads, while merging various pharmacophoric motifs of natural and synthetic caspase activators via optimized one-pot Passerini reaction conditions. The prepared compounds resulting from Passerini reaction were screened for their cytotoxic activities against colorectal Caco-2 and liver HepG-2 cancer cells compared to normal fibroblasts utilizing MTT assay. Notably, all compounds exhibited promising low-range submicromolar IC50 against the studied cancer cell lines, with outstanding tumor selectivity (SI values up to 266). Hence, they were superior to 5-fluorouracil. Notably, 7a, 7g, and 7j conferred the highest potencies against Caco-2 and HepG-2 cells and were selected for further mechanistic studies. Caspas-3/7 activation assay of the hit compounds and flow cytometric analysis of the treated apoptotic cancer cells demonstrated their significant caspase activation potential (up to 4.2 folds) and apoptotic induction capacities (up to 58.7%). Further assessment of Bcl2 expression was performed being a physiological caspase-3 substrate. Herein, the three studied Passerini adducts were able to downregulate Bcl2 in the treated Caco-2 cells. Importantly, the mechanistic studies results of the three hits echoed their preliminary MTT antiproliferative potencies data highlighting their caspase-3 dependent apoptotic induction. Finally, the in silico predicted physicochemical and pharmacokinetic profiles, as well as ligand efficiency metrics were drug-like.

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Section: Resultsmentioning

confidence: 99%

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Ayoup

Wahby

Hamid

et al. 2022

Sci Rep

Self Cite

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“…Later, Yun Young Go et al [ 104 ] and Kinzhalov et al [ 105 ] showed that mild heating (30–60 °C) led to obtaining 1,2,4-oxadiazoles with unprotected primary arylamino functionalities. At the same time, Teleb with colleagues successfully performed the reaction with salicylic esters at RT [ 106 ]. One more limitation is the presence of a high CH-acidic methylene group.…”

Section: Base-induced Cyclodehydration Of O -Acyla...mentioning

confidence: 99%

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Baykov

Shetnev

Semenov

et al. 2023

IJMS

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1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work--up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.

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“…In addition, 1,2,4-oxadiazole analogues have the advantages of high stability in aqueous solution and resistance to the hydrolysis reaction and are even stable in concentrated sulfuric acid, thus an oxadiazole ring is usually used as bio-isosteres of carbonyl-containing groups (such as esters, amides, and carbamates) in drug discovery and development . Mounting research studies reveal a broad spectrum of biological activities of 1,2,4-oxadiazole derivatives, including the anticancer activity, − antioxidant effect, antibacterial activity, , antiviral activity, anti-inflammatory activity, − and antiparasitic activity, thus attracting growing attention to the role of 1,2,4-oxadiazole heterocyclic analogues in drug discovery …”

Section: Introductionmentioning

confidence: 99%

“…44 In addition, 1,2,4oxadiazole analogues have the advantages of high stability in aqueous solution and resistance to the hydrolysis reaction and are even stable in concentrated sulfuric acid, thus an oxadiazole ring is usually used as bio-isosteres of carbonyl-containing groups (such as esters, amides, and carbamates) in drug discovery and development. 45 Mounting research studies reveal a broad spectrum of biological activities of 1,2,4oxadiazole derivatives, including the anticancer activity, 46−50 antioxidant effect, 50 antibacterial activity, 51,52 antiviral activity, 53 anti-inflammatory activity, 54−56 and antiparasitic activity, 57 thus attracting growing attention to the role of 1,2,4oxadiazole heterocyclic analogues in drug discovery. 58 In the previous work, we have obtained a series of novel and effective Nrf2 activators with the 1,2,4-oxadiazole structure (see Figure 1), which exhibited remarkable therapeutic effects on inflammation-related diseases including dextran sulfate sodium (DSS)-induced colitis, 59,60 acetaminophen (APAP)induced acute liver injury, 61 and 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced PD.…”

Section: Introductionmentioning

confidence: 99%

Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome

Dai

Chen

et al. 2022

J. Med. Chem.

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1,2,4-Oxadiazole derivatives, a class of Nrf2-ARE activators, exert an extensive therapeutic effect on inflammation, cancer, neurodegeneration, and microbial infection. Among these analogues, DDO-7263 is the most potent Nrf2 activator and used as the core structure for bioactive probes to explore the precise mechanism. In this work, we obtained compound 7, a mimic of DDO-7263, and biotin-labeled and fluorescein-based probes, which exhibited homologous biological activities to DDO-7263, including activating Nrf2 and its downstream target genes, anti-oxidative stress, and anti-inflammatory effects. Affinity chromatography and mass analysis techniques revealed Rpn6 as the potential target protein regulating the Nrf2 signaling pathway. In vitro affinity experiments further confirmed that DDO-7263 upregulated Nrf2 through binding to Rpn6 to block the assembly of 26S proteasome and the subsequent degradation of ubiquitinated Nrf2. These results indicated that Rpn6 is a promising candidate target to activate the Nrf2 pathway for protecting cells and tissues from oxidative, electrophilic, and exogenous microbial stimulation.

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Beyond direct Nrf2 activation; reinvestigating 1,2,4-oxadiazole scaffold as a master key unlocking the antioxidant cellular machinery for cancer therapy

Cited by 26 publications

References 118 publications

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Structure optimization of new tumor-selective Passerini α-acyloxy carboxamides as Caspase-3/7 activators

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome

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