Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity

Abdel-Aziz, Amal Kamal; Dokla, Eman M.E.; Abouzid, Khaled A.M.; Minucci, Saverio

doi:10.1016/j.bcp.2022.115316

Cited by 8 publications

(3 citation statements)

References 48 publications

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“…This aligns with the recent anticancer strategy of inducing ERS to promote cancer cell apoptosis. [74,75] By modulating the ERS signaling pathway, avasimibe plays a crucial role in tumor aggression, migration, proliferation, and death, offering a new mechanistic perspective for GBC treatment. [76,77] Avasimibe significantly reduced the proliferation, migration, and invasion abilities of GBC cells, similar to its effects in other cancer types, such as chronic myeloid leukemia and prostate cancer, where it inhibits tumor growth through various mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics

Hong,

Abudukeremu,

She

et al. 2024

J Biochem & Molecular Tox

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The aim of this investigation was to evaluate the differential expression of the sterol O‐acyltransferase 1 (SOAT1) protein in gallbladder cancer tissues and cells, investigate the impact of Avastin on the proliferation, migration, invasion capabilities of gallbladder cancer cells, and its potential to induce cell apoptosis. Immunohistochemical analysis of samples from 145 gallbladder cancer patients was conducted, along with analysis of SOAT1 protein, mRNA expression levels, and cholesterol content in gallbladder cancer cell lines SGC‐996, NOZ, and gallbladder cancer (GBC)‐SD using Western blot and q‐PCR techniques. Furthermore, the effects of Avastin on the proliferation, migration, and invasion capabilities of these gallbladder cancer cell lines were studied, and its ability to induce cell apoptosis was evaluated using flow cytometry, Western blot, and immunohistochemical methods. Additionally, gene expression and pathway analysis were performed, and the synergistic therapeutic effects of Avastin combined with gemcitabine were tested in a gallbladder cancer xenograft model. The study found that SOAT1 expression was significantly upregulated in GBC tissues and positively correlated with lymph node metastasis and TNM staging. In vitro experiments demonstrated that Avastin significantly inhibited the proliferation, migration, and invasion capabilities of SGC‐996 and GBC‐SD cell lines and induced apoptosis. RNA sequencing analysis revealed multiple differentially expressed genes in cells treated with Avastin, primarily enriched in biological pathways such as signaling transduction, malignant tumors, and the immune system. In vivo, experiments confirmed that Avastin could effectively suppress tumor growth in a gallbladder cancer xenograft model and enhanced the treatment efficacy when used in combination with gemcitabine. Overall, these findings provide new insights and strategies for targeted therapy in gallbladder cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics

Hong,

Abudukeremu,

She

et al. 2024

J Biochem & Molecular Tox

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“…It is well known that nitrogen-containing heterocycles are privileged structures in medicinal chemistry because their derivatives have various biological properties [ 1 ]. The importance of nitrogen heterocycles as key pharmacophoric moieties lies in the synthesis of novel anticancer compounds [ 2 , 3 , 4 , 5 , 6 ]. Indeed, the presence of different nitrogen electron-donor atoms in the structure improves the interaction with target proteins, enzymes, and receptors through the formation of several types of interactions, such as hydrogen bonds, dipole-dipole, hydrophobic interactions, van der Waals forces, and π-stacking interactions.…”

Section: Introductionmentioning

confidence: 99%

Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development

Buravchenko,

Shchekotikhin

2023

Pharmaceuticals

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N-Oxides of heterocyclic compounds are the focus of medical chemistry due to their diverse biological properties. The high reactivity and tendency to undergo various rearrangements have piqued the interest of synthetic chemists in heterocycles with N-oxide fragments. Quinoxaline 1,4-dioxides are an example of an important class of heterocyclic N-oxides, whose wide range of biological activity determines the prospects of their practical use in the development of drugs of various pharmaceutical groups. Derivatives from this series have found application in the clinic as antibacterial drugs and are used in agriculture. Quinoxaline 1,4-dioxides present a promising class for the development of new drugs targeting bacterial infections, oncological diseases, malaria, trypanosomiasis, leishmaniasis, and amoebiasis. The review considers the most important methods for the synthesis and key directions in the chemical modification of quinoxaline 1,4-dioxide derivatives, analyzes their biological properties, and evaluates the prospects for the practical application of the most interesting compounds.

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Novel Ag(I)‐based 1,2,4‐Oxadiazole Complexes: Synthesis, X‐Ray Crystal Structure, and Biological Evaluation as Anticancer Candidates

Ayoup,

Alashhab,

Soliman

et al. 2024

Applied Organom Chemis

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The 3,5‐diaryl‐1,2,4‐oxadiazole scaffolds 2 and 3 were synthesized and used as ligands to obtain three novel Ag(I) complexes 4–6. The structure of the Ag(I) complexes 4–6 has been confirmed by single crystal X‐ray diffraction. Complex 4 has the dinuclear formula [Ag(2)(NO3)]2. 5 and 6 are monomeric complexes having the formula [Ag(3)2(NO3)] and [Ag(3)2]ClO4, respectively. In vitro, trypsin, ALDH2, and iNOS inhibition activities were assessed for the free ligands and their Ag(I) complexes. Interestingly, Ag(I) complexes 4–6 revealed more prominent trypsin inhibitory activity than the ligands 2 and 3. The oxadiazole derivative 3 and its Ag(I) complex (6) showed significant ALDH2 inhibition (45% and 55%, respectively). Complex 6 (IC50 = 35.61 μM) surpassed its 1,2,4‐oxadiazole ligand 3 (IC50 = 88 μM) and evidenced the most prominent ALDH2 inhibitory activity. The oxadiazole derivative 3 and its corresponding Ag(I) complexes 5 and 6 showed significant iNOS inhibition (77.77%, 84.12%, and 84.15%, respectively). With IC50 values of 18.13, 18.15, and 13.96 μM, respectively, complex 6 is the most potent against iNOS, surpassing the reference standard.

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Discovery of EMD37, a 1,2,4-oxadiazole derivative, as a novel endoplasmic reticulum stress inducer with potent anticancer activity

Cited by 8 publications

References 48 publications

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics

SOAT1 in gallbladder cancer: Clinicopathological significance and avasimibe therapeutics

Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development

Novel Ag(I)‐based 1,2,4‐Oxadiazole Complexes: Synthesis, X‐Ray Crystal Structure, and Biological Evaluation as Anticancer Candidates

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