83730-53-4 | Page 3 of 5 | Heterocyclic Building Blocks-Benzoxazole

Jiang, Hui’s team published research in Frontiers in Pharmacology in 2022 | CAS: 83730-53-4

Bismuth reduces cisplatin-induced nephrotoxicity via enhancing glutathione conjugation and vesicular transport. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

(2S)-2-Amino-4-(butylsulfonimidoyl)butanoic acid (BD136012) is a building block containing a sulfoximine group. Several CDK and ATR inhibitors have exemplified the utilization of the NH sulfoximine group as abioisostere for a sulfonamide group to overcome the main project hurdles of aqueous solubility, sulfonamide-mediated off-target activity and IP. Moreover, its NH group could be expediently further functionalized through Buchwald-Hartwig coupling reaction and multifarious nucleophilic reactions.. Recommended Products is: 4381-25-3 and 1621962-30-8.

Bismuth drugs have long been used against gastrointestinal diseases, especially the gastric infection of Helicobacter pylori. Cisplatin is a widely used anticancer drug that tends to accumulate at renal proximal tubules and causes severe nephrotoxicity. It was found that bismuth pretreatment reduces cisplatin-induced nephrotoxicity, but the mechanism of action remains unclear. To understand bismuth’s effect on renal tubules, we profiled the proteomic changes in human proximal tubular cells (HK-2) upon bismuth treatment. We found that bismuth induced massive glutathione biosynthesis, glutathione S-transferase activity, and vesicular transportation, which compartmentalizes bismuth to the vesicles and forms bismuth-sulfur nanoparticles. The timing of glutathione induction concurs that of bismuth-induced cisplatin toxicity mitigation in HK-2, and bismuth enhanced cisplatin sequestration to vesicles and incorporation into bismuth-sulfur nanoparticles. Finally, we found that bismuth mitigates the toxicity of general soft metal compounds but not hard metal compounds or oxidants. It suggests that instead of through oxidative stress reduction, bismuth reduces cisplatin-induced toxicity by direct sequestration.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Wang, Xu’s team published research in Chemical Research in Toxicology in 2022-02-21 | CAS: 83730-53-4

Cysteine-Based Protein Covalent Binding and Hepatotoxicity Induced by Emodin. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Emodin (EMD) is a major ingredient of Polygonum multiflorum Thunb. (PMT), which has shown adverse liver reactions. Despite multiple pharmacol. activities, EMD is reported to show various toxicities. Our early study demonstrated the reactivity of EMD to glutathione. This study aimed to determine the covalent interaction of hepatic protein with EMD and the correlation of the protein modification with hepatotoxicity induced by EMD. EMD-derived protein adduction was detected in an incubation mixture containing mouse liver homogenates and EMD. Such protein adduction was also observed in hepatic protein obtained from mice exposed to EMD. The protein covalent binding occurred in time- and dose-dependent manners. Pre-treatment of L-buthionine-sulfoximine significantly potentiated EMD-induced adduction and hepatotoxicity caused by EMD and lipopolysaccharide co-treatment. As expected, EMD-derived protein modification was observed in mouse primary hepatocytes treated with EMD. The increase in EMD exposure concentration intensified EMD-derived protein adduction and increased EMD-induced cell death. The susceptibility of hepatocytes to EMD cytotoxicity and the intensity of EMD-induced protein adduction were attenuated by the co-treatment of hepatocytes with N-acetyl cysteine. A good association of protein modification with hepatotoxicity induced by EMD was illustrated, which facilitates the understanding of the mechanism of hepatotoxicity induced by EMD.

Cysteine-Based Protein Covalent Binding and Hepatotoxicity Induced by Emodin. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Hayashima, Kazuki’s team published research in Journal of Biological Chemistry in 2022-03-31 | CAS: 83730-53-4

Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosis. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Ferroptosis is an iron-dependent mode of cell death caused by excessive oxidative damage to lipids. Lipid peroxidation is normally suppressed by glutathione peroxidase 4, which requires reduced glutathione. Cystine is a major resource for glutathione synthesis, especially in cancer cells. Therefore, cystine deprivation or inhibition of cystine uptake promotes ferroptosis in cancer cells. However, the roles of other mols. involved in cysteine deprivation-induced ferroptosis are unexplored. We report here that the expression of gamma-glutamyltransferase 1 (GGT1), an enzyme that cleaves extracellular glutathione, determines the sensitivity of glioblastoma cells to cystine deprivation-induced ferroptosis at high cell d. (HD). In glioblastoma cells expressing GGT1, pharmacol. inhibition or deletion of GGT1 suppressed the cell d.-induced increase in intracellular glutathione levels and cell viability under cystine deprivation, which were restored by the addition of cysteinylglycine, the GGT product of glutathione cleavage. On the other hand, cystine deprivation induced glutathione depletion and ferroptosis in GGT1-deficient glioblastoma cells even at an HD. Exogenous expression of GGT1 in GGT1-deficient glioblastoma cells inhibited cystine deprivation-induced glutathione depletion and ferroptosis at an HD. This suggests that GGT1 plays an important role in glioblastoma cell survival under cystine-limited and HD conditions. We conclude that combining GGT inhibitors with ferroptosis inducers may provide an effective therapeutic approach for treating glioblastoma.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Arczewska, Katarzyna D.’s team published research in DNA Repair in 2020-11-30 | CAS: 83730-53-4

hMTH1 and GPX1 expression in human thyroid tissue is interrelated to prevent oxidative DNA damage. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Oxidative stress (OS) is recognized as disturbance of cellular equilibrium between reactive oxygen species (ROS) formation and their elimination by antioxidant defense systems. One example of ROS-mediated damage is generation of potentially mutagenic DNA precursor, 8-oxodGTP. In human cells genomic 8-oxodGTP incorporation is prevented by the MutT homolog 1 (MTH1 or hMTH1 for human MTH1) protein. Above observations led to the development of hMTH1 inhibitors as novel anticancer therapeutics. In the current study we present extensive anal. of oxidative stress responses determining sensitivity to hMTH1 deficiency in cultured thyroid cells. We observe here that hMTH1 depletion results in downregulation of several glutathione-dependent OS defense system factors, including GPX1 and GCLM, making some of the tested thyroid cell lines highly dependent on glutathione levels. This is evidenced by the increased ROS burden and enhanced proliferation defect after combination of hMTH1 siRNA and glutathione synthesis inhibition. Moreover, due to the lack of data on hMTH1 expression in human thyroid tumor specimens we decided to perform detailed anal. of hMTH1 expression in thyroid tumor and peri-tumoral tissues from human patients. Our results allow us to propose here that anticancer activity of hMTH1 suppression may be boosted by combination with agents modulating glutathione pool, but further studies are necessary to precisely identify backgrounds susceptible to such combination treatment.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Zhong, Hao’s team published research in Advanced Healthcare Materials in 2021-10-06 | CAS: 83730-53-4

Versatile Nanodrugs Containing Glutathione and Heme Oxygenase 1 Inhibitors Enable Suppression of Antioxidant Defense System in a Two-Pronged Manner for Enhanced Photodynamic Therapy. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

The antioxidant defense system in malignant cells, which involves antioxidant enzymes and antioxidant mols., is an innate barrier to photodynamic therapy (PDT). Because of the complexity of the endogenous antioxidant mechanisms of these cells, simply inhibiting individual antioxidant pathways has a limited effect on improving the lethality of ROS. To enhance the efficacy of PDT for tumor treatment, a versatile nanoparticle (NP)-based drug is developed, which the authors call PZB NP, containing the glutathione inhibitor L-buthionine sulfoximine (BSO) and the heme oxygenase 1 (HO-1) inhibitor protoporphyrin zinc(II) (ZnPP) to suppress the innate antioxidant defense system of cancer cells in a two-pronged manner. BSO reduces intracellular glutathione levels to minimize ROS elimination and protein protection during PDT, and ZnPP inhibits the ROS-stimulated upregulation of the antioxidant HO-1, thus preventing ROS removal by cells after PDT. Thus, BSO and ZnPP synergistically suppress the antioxidant defense systems of cancer cells both during and after protoporphyrin-IX-mediated PDT in a two-pronged manner, resulting in tumor cell death through excess oxidative pressure. The results demonstrate that the construction of nanodrugs having dual antioxidation defense suppression properties is a promising route for the development of highly efficient ROS-based therapies.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Yu, Xie-an’s team published research in Theranostics in 2020 | CAS: 83730-53-4

A cancer-specific activatable theranostic nanodrug for enhanced therapeutic efficacy via amplification of oxidative stress. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Rationale: Despite considerable advances, the reactive oxygen species (ROS)-mediated cancer treatment suffers from the problems of up-regulation of adaptive antioxidants in cancer cells as well as side effects to normal cells. Therefore, development of a new generation of cancer-specific nanomedicine capable of amplifying oxidative stress would be of great interest for accurate and effective cancer treatment. Methods: Herein, transferrin (Tf)-decorated, dihydroartemisinin (DHA), L-buthionine-sulfoximine (BSO), and CellROX-loaded liposomal nanoparticles (Tf-DBC NPs) were developed for precise cancer theranositcs. Tf-DBC NPs could specifically recognize cancer cells via Tf-Tf receptor binding and be uptaken into the lysosomes of cancer cells, where Tf-DBC NPs were activated to release Fe(II), DHA, and BSO. ROS was generated by DHA in the presence of Fe(II), and GSH was depleted by BSO to disrupt the redox balance in cancer cells. Furthermore, CellROX, as a fluorescent probe for imaging of intracellular oxidative stress, was used to monitor the therapeutic efficacy. Results: The integration of Tf, DHA, and BSO into the acidic pH-responsive liposomes selectively and effectively killed cancer cells and prevented the oxidative injury to normal cells. The high oxidative state was visualized at the tumor site and the amplification of oxidative stress enabled tumor eradication by Tf-DBC NPs, demonstrating the successful implementation of this novel strategy in vivo. Conclusion: Our study provides a new paradigm for the design of ROS-mediated therapeutics and offers a promising perspective for precise cancer treatment.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Schweikl, Helmut’s team published research in Dental Materials in 2021-01-31 | CAS: 83730-53-4

HEMA-induced oxidative stress inhibits NF-¦ÊB nuclear translocation and TNF release from LTA- and LPS-stimulated immunocompetent cells. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

The release of inflammatory cytokines from antigen-stimulated cells of the immune system is inhibited by resin monomers such as 2-hydroxyethyl methacrylate. Although the formation of oxidative stress in cells exposed to HEMA is firmly established, the mechanism behind the inhibited cytokine secretion is only partly known. The present investigation presents evidence regarding the role of HEMA-induced oxidative stress in the secretion of the pro-inflammatory cytokine TNF¦Á from cells exposed to the antigens LTA or LPS of cariogenic microorganisms using BSO or NAC to inhibit or stabilize the amounts of the antioxidant glutathione. RAW264.7 mouse macrophages were treated with LTA, LPS or HEMA in the presence of BSO or NAC for 1h or 24h. Secretion of TNF¦Á from cell cultures was analyzed by ELISA, and the formation of reactive oxygen or nitrogen species was determined by flow cytometry. Protein expression was detected by Western blotting. The release of TNF¦Á in both LTA- and LPS-exposed cells was decreased by HEMA, and this concentration-dependent inhibitory effect was amplified by BSO or NAC. LTA- and LPS-stimulated expression of the redox-sensitive transcription factor NF-¦ÁB (p65) in cell nuclei decreased in the presence of HEMA because the translocation of p65 from the cytosol was prevented by oxidative stress specifically increased by the monomer. A disturbance of the cellular redox balance, particularly induced by HEMA, is a crucial factor in the inhibition of LTA- and LPS-stimulated signalling pathways leading to TNF¦Á secretion.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Liu, Min’s team published research in Journal of Materials Chemistry B: Materials for Biology and Medicine in 2021 | CAS: 83730-53-4

Glutathione-triggered nanoplatform for chemodynamic/metal-ion therapy. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

The integration of metal-ion therapy and hydroxyl radical ( OH)-mediated chemodynamic therapy (CDT) holds great potential for anticancer treatment with high specificity and efficiency. Herein, Ag nanoparticles (Ag NPs) were enveloped with Cu2+-based metal-organic frameworks (MOFs) and further decorated with hyaluronic acid (HA) to construct a glutathione (GSH)-activated nanoplatform (Ag@HKU-HA) for specific chemodynamic/metal-ion therapy. The obtained nanoplatform could avoid the premature leakage of Ag in circulation, but realize the release of Ag at the tumor site owing to the degradation of external MOFs triggered by Cu2+-reduced glutathione. The generated Cu+ could catalyze endogenous H2O2 to the highly toxic OH by a Fenton-like reaction. Meanwhile, Ag NPs were oxidized to toxic Ag ions in the tumor environment. As expect, the effect of CDT combined with metal-ion therapy exhibited an excellent inhibition of tumor cells growth. Therefore, this nanoplatform may provide a promising strategy for on-demand site-specific cancer combination treatment.

Glutathione-triggered nanoplatform for chemodynamic/metal-ion therapy. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Dong, Ziliang’s team published research in Chem in 2020-06-11 | CAS: 83730-53-4

Synthesis of CaCO3-Based Nanomedicine for Enhanced Sonodynamic Therapy via Amplification of Tumor Oxidative Stress. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Development of multifunctional stimuli-responsive nanomedicine is appealing for effective cancer treatment. Herein, we utilize the biocompatible CaCO3 nanoparticles as the template to guide the formation of pH-dissociable hollow coordination nanostructures, in which meso-tetra-(4-carboxyphenyl)porphine (TCPP), a sonosensitizer, acts as the organic bridging mol. and ferric ion serves as the metallic center. L-buthionine sulfoximine (BSO), an inhibitor for glutathione (GSH) biosynthesis, can be simultaneously loaded during the preparation of TCPP-Fe@CaCO3, obtaining BSO-TCPP-Fe@CaCO3 with pH-responsive dissociation to endow fast release of Ca2+ and BSO under an acidic tumor microenvironment. Such BSO-TCPP-Fe@CaCO3 confers synergistic oxidative stress amplification via intracellular Ca2+-overloading-induced mitochondria damage, BSO-mediated GSH depletion, and TCPP-mediated sonodynamic therapy (SDT), leading to remarkable cell death. Consequently, tumors on the mice treated with BSO-TCPP-Fe@CaCO3 administration and subsequent ultrasound exposure are effectively suppressed. Our work thus highlights a facile strategy to prepare pH-dissociable nanomedicine for effective SDT treatment of tumors via triple amplification of tumor oxidative stress.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Wei, Yawen’s team published research in Journal of Colloid and Interface Science in 2022-01-15 | CAS: 83730-53-4

Reactive oxygen species / photothermal therapy dual-triggered biomimetic gold nanocages nanoplatform for combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

With the continuous development of cancer nanotechnol., an important trend in the research is to combine the broad application prospects of functional nanomaterials with recent biol. discoveries and technol. advances. Herein, a cancer cell membrane-camouflaged gold nanocage loading doxorubicin (DOX) and L-buthionine sulfoximine (BSO) (denoted as m@Au-D/B NCs) was constructed as an innovative nanoplatform to confer promising cancer combination therapy by evoking effective ferroptosis and immune responses. Briefly, the loading of BSO and DOX could induce ferroptosis through simultaneous effective glutathione (GSH) consumption and reactive oxygen species (ROS) accumulation. Gold nanocages (AuNCs) with distinct anti-tumor application performance was utilized as ideal nanocarrier for drug loading, evoking photothermal effects and photochem. catalysis to generate more ROS under near-IR (NIR) irradiation Moreover, m@Au-D/B NCs-mediated photothermal therapy (PTT) combined with ROS production could repolarize the tumor-associated macrophages (TAMs) from pro-tumor (M2) phenotype to anti-tumor (M1) phenotype, thus improving tumor-suppressive immune environment and then promoting the activation of effector cells and release of pro-inflammatory cytokines, in which the antitumor responses were evoked robustly in a methodical approach. The anti-tumor effects in vivo implied that m@Au-D/B NCs could significantly inhibit tumor growth without severe toxicity. Hence, this homotypic targeting nanosystem could offer an auspicious anticancer access by triggering combination cancer therapy via ferroptosis and tumor-associated macrophage repolarization mechanism.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem