83730-53-4 | Heterocyclic Building Blocks-Benzoxazole

Knany, Alaa’s team published research in Free Radical Biology & Medicine in 2020-11-20 | CAS: 83730-53-4

S-nitrosocysteine and glutathione depletion synergize to induce cell death in human tumor cells: Insights into the redox and cytotoxic mechanisms. 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.

Nitric oxide (NO)-dependent signaling and cytotoxic effects are mediated in part via protein S-nitrosylation. The magnitude and duration of S-nitrosylation are governed by the two main thiol reducing systems, the glutathione (GSH) and thioredoxin (Trx) antioxidant systems. In recent years, approaches have been developed to harness the cytotoxic potential of NO/nitrosylation to inhibit tumor cell growth. However, progress in this area has been hindered by insufficient understanding of the balance and interplay between cellular nitrosylation, other oxidative processes and the GSH/Trx systems. In addition, the mechanistic relationship between thiol redox imbalance and cancer cell death is not fully understood. Herein, we explored the redox and cellular effects induced by the S-nitrosylating agent, S-nitrosocysteine (CysNO), in GSH-sufficient and -deficient human tumor cells. We used L-buthionine-sulfoximine (BSO) to induce GSH deficiency, and employed redox, biochem. and cellular assays to interrogate mol. mechanisms. We found that, under GSH-sufficient conditions, a CysNO challenge (100-500¦ÌM) results in a marked yet reversible increase in protein S-nitrosylation in the absence of appreciable S-oxidation In contrast, under GSH-deficient conditions, CysNO induces elevated and sustained levels of both S-nitrosylation and S-oxidation Experiments in various cancer cell lines showed that administration of CysNO or BSO alone commonly induce minimal cytotoxicity whereas BSO/CysNO combination therapy leads to extensive cell death. Studies in HeLa cancer cells revealed that treatment with BSO/CysNO results in dual inhibition of the GSH and Trx systems, thereby amplifying redox stress and causing cellular dysfunction. In particular, BSO/CysNO induced rapid oxidation and collapse of the actin cytoskeletal network, followed by loss of mitochondrial function, leading to profound and irreversible decrease in ATP levels. Further observations indicated that BSO/CysNO-induced cell death occurs via a caspase-independent mechanism that involves multiple stress-induced pathways. The present findings provide new insights into the relationship between cellular nitrosylation/oxidation, thiol antioxidant defenses and cell death. These results may aid future efforts to develop NO/redox-based anticancer approaches.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Sun, Haitao’s team published research in Journal of Materials Chemistry B: Materials for Biology and Medicine in 2020 | CAS: 83730-53-4

Near-infrared photothermal liposomal nanoantagonists for amplified cancer photodynamic therapy. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Photodynamic therapy (PDT) has been demonstrated to be a promising strategy for the treatment of cancer, while its therapeutic efficacy is often compromised due to excessive concentrations of glutathione (GSH) as a reactive oxygen species (ROS) scavenger in cancer cells. Herein, we report the development of near-IR (NIR) photothermal liposomal nanoantagonists (PLNAs) for amplified PDT through through the reduction of intracellular GSH biosynthesis. Such PLNAs were constructed via encapsulating a photosensitizer, indocyanine green (ICG) and a GSH synthesis antagonist, L-buthionine sulfoximine (BSO) into a thermal responsive liposome. Under NIR laser irradiation at 808 nm, PLNAs generate mild heat via a ICG-mediated photothermal conversion effect, which leads to the destruction of thermal responsive liposomes for a controlled release of BSO in a tumor microenvironment, ultimately reducing GSH levels. This amplifies intracellular oxidative stresses and thus synergizes with PDT to afford an enhanced therapeutic efficacy. Both in vitro and in vivo data verify that PLNA-mediated phototherapy has an at least 2-fold higher efficacy in killing cancer cells and inhibiting tumor growth compared to sole PDT. This study thus demonstrates a NIR photothermal drug delivery nanosystem for amplified photomedicine.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Zhang, Shiyu’s team published research in Toxicology and Applied Pharmacology in 2022-05-15 | CAS: 83730-53-4

DNA damage by reactive oxygen species resulting from metabolic activation of 8-epidiosbulbin E acetate in vitro and in vivo. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

8-Epidiosbulbin E acetate (EEA), a furan-containing diterpenoid lactone, is one of main component of Dioscorea bulbifera L.(DBL). It has been reported that EEA induces severe hepatotoxicity in mice and that its hepatotoxicity is associated with metabolic activation. The present study demonstrated that exposure to EEA (50, 100 or 200 ¦ÌM) induced DNA damage, including significant DNA fragmentation, increases of tail DNA and olive tail moment, H2AX phosphorylation and PARP-1 activation, in cultured mouse primary hepatocytes. Similar observation was obtained in mice administered EEA at 50, 100 or 200 mg/kg. Pre-treatment with 10 ¦ÌM ketoconazole (KTC), 200 ¦ÌM vitamin C (VC), or 200 ¦ÌM glutathione Et ester (GSH-OEt) reversed the over-production of reactive oxygen species (ROS) induced by EEA and attenuated susceptibility of hepatocytes to EEA-induced cytotoxicity and DNA damage in mouse primary hepatocytes. In contrast, pre-treatment with 1.0 mM L-buthionine sulfoximine (BSO) potentiated over-production of ROS, cytotoxicity and DNA damage induced by EEA. In summary, EEA induced DNA damage in cultured primary hepatocytes and the liver of mice. ROS, possibly along with DNA alkylation, participated in the observed DNA damage.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Benhusein, Ghazalla’s team published research in Journal of Advances in Medical and Pharmaceutical Sciences in 2020 | CAS: 83730-53-4

Genotoxic effect of arsenate and arsenite in human hacat cells in culture using comet assay. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Arsenic is an environmental chem. of toxicol. concern today since it is a human genotoxin and chronic exposure is associated with development of cancers, including skin. Inorganic arsenate is metabolically reduced to arsenite by glutathione (GSH) prior to methylation. The aim of this study was to determine the relative toxic effects of arsenate and arsenite in HaCat cells (immortalized human keratinocytes) in vitro by measuring cytotoxicity, DNA damage, depletion of glutathione and apoptotic and necrotic events. HaCat cells were treated with arsenate and arsenite (10¦ÌM) for DNA damage detection using Comet assay and cytotoxicity (10, 60 and 100¦ÌM) all measured at 24 h. In some experiment arsenate or arsenite (10¦ÌM) was added at the same time as BSO 10¦ÌM for 24 h, and GSH levels were measured by HPLC with fluorescence detection. Flow cytometry was used to investigate apoptotic and necrotic events following arsenate and arsenite (10¦ÌM) treatment for 24 h. Arsenate and arsenite at 60 and 100¦ÌM, but not 10¦ÌM, reduced the number of adherent viable cells with time. Therefore, DNA damage could only be measured at 10¦ÌM as at higher concentrations the cells did not produce classical Comets but showed fragmentation. DNA damage was significantly (p < 0.001) increased in cells treated for 24 h with 10¦ÌM arsenate and arsenite compared to control. GSH levels were significantly increased in HaCat cells treated with10¦ÌM arsenate and arsenite (p <0.05, p < 0.001, resp.) compared to control. Cells treated with buthionine sulfoximine (BSO) at the same time as arsenate had increased GSH levels (p < 0.001), but arsenite and BSO did not increase cellular GSH. Arsenate and arsenite increased apoptosis, and arsenate increased necrosis, although none of the values reached statistical significance. Arsenite was more cytotoxic than arsenate. Arsenate and arsenite are known to produce oxidative stress involving ROS formation and depletion of glutathione. The increase in GSH levels at low doses of arsenate and arsenite, and by arsenate even in the presence of BSO. Genotoxic effect of arsenate and arsenite in human hacat cells in culture using comet assay. 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

Cruz, Adriana’s team published research in Antioxidants in 2020 | CAS: 83730-53-4

Polyurea dendrimer folate-targeted nanodelivery of L-buthionine sulfoximine as a tool to tackle ovarian cancer chemoresistance. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Ovarian cancer is a highly lethal disease, mainly due to chemoresistance. Our previous studies on metabolic remodeling in ovarian cancer have supported that the reliance on glutathione (GSH) bioavailability is a main adaptive metabolic mechanism, also accounting for chemoresistance to conventional therapy based on platinum salts. In this study, we tested the effects of the in vitro inhibition of GSH synthesis on the restoration of ovarian cancer cells sensitivity to carboplatin. GSH synthesis was inhibited by exposing cells to L-buthionine sulfoximine (L-BSO), an inhibitor of ¦Ã-glutamylcysteine ligase (GCL). Given the systemic toxicity of L-BSO, we developed a new formulation using polyurea (PURE) dendrimers nanoparticles (L-BSO@PUREG4-FA2), targeting LBSO delivery in a folate functionalized nanoparticle.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Ran, Shanshan’s team published research in Ecotoxicology and Environmental Safety in 2022-04-01 | CAS: 83730-53-4

NaAsO2 decreases GSH synthesis by inhibiting GCLC and induces apoptosis through Hela cell mitochondrial damage, mediating the activation of the NF-¦ÊB/miR-21 signaling pathway. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Cervical cancer is the fourth most common cancer in women worldwide, and arsenic has a certain effect in solid tumor chemotherapy. As the rate-limiting enzyme subunit of GSH synthesis, GCLC may be an important target for arsenic to induce apoptosis through mitochondrial apoptosis pathway to exert anti-tumor effect. NF-¦ÊB plays an important role in the occurrence and development of cervical cancer and can regulate the expression of GCLC. miR-21 is a potential biomarker of cervical cancer, which can induce apoptosis through ROS regulated the mitochondrial pathway of cells. However, the role of miR-21 in the mitochondrial pathway of cervical cancer cells induced by NaAsO2 through NF-¦ÊB/GCLC and GSH synthesis regulated oxidative stress is rarely reported. Therefore, the purpose of this study was to investigate whether NaAsO2 might induce mitochondrial damage and apoptosis of cervical cancer cells through NF-¦ÊB/ miR-21 /GCLC induced oxidative stress, and play the anti-tumor role of arsenic as a potential drug for the treatment of cervical cancer. Hela cells were treated with different concentrations of NaAsO2, D, -Buthionine-(SR)-sulfoximine (BSO), I¦ÊB¦Á inhibitor (BAY 11-7082) and miR-21 Inhibitor. CCK-8 assay, Western Blot, qRT PCR, immunofluorescence, transmission electron microscopy, mitochondrial Membrane Potential Assay Kit with JC-1,2¡ä,7¡ä-Dichlorofluorescin diacetate fluorescent probe and Annexin V-FITC were used to measure cell activity, GSH and ROS, mitochondrial morphol. and membrane potential (¦¤¦·m), protein and mRNA expression of GCLC, GCLM, p65, I¦ÊB¦Á, p-P65, p-I ¦ÊB¦Á, Bcl-2, BAX, Caspase3, cleaved-caspase3 and miR-21. Compared with the control group, with the gradual increasing dose of NaAsO2, cell viability was considerable reduced, and increased rate of apoptosis, intracellular GSH level was decreased significantly, ROS was increased, mitochondrial structure was damaged, mitochondrial membrane potential ¦¤¦·m and Bcl2/BAX lowered, the expression of Caspase3 and cleaved-caspase3 were significantly increased, resulting in mitochondrial apoptosis. When Hela cells were treated with 15, 20, and 25 ¦Ìmol/L NaAsO2, the mRNA and protein levels of GCLC and GCLM were reduced, the expression of p65 in the nucleus was increased, the expression of p-p65/p65, p-I¦ÊB¦Á/I¦ÊB¦Á and miR-21 were significantly increased. When BSO increased the inhibitory effect of NaAsO2 on GCLC, Compared with NaAsO2 group, the ¦¤¦·m and protein of Bcl-2/BAX, caspase3 and cleaved-capsase3 were increased. When BAY 11-7082 combined with NaAsO2 co-treated, compared with the NaAsO2 group, the protein and mRNA expression of GCLC was increased, NaAsO2-increased expression level of miR-21 was suppressed, and the ¦¤¦·m and cell viability were higher. In addition, compared with the combination of NaAsO2 and miR-21NC, the protein expression of GCLC was increased, the ¦¤¦·m and cell viability reduction were alleviated by miR-21 Inhibitor combined with NaAsO2. NaAsO2 may lead to ROS accumulation in Hela cells and trigger mitochondrial apoptosis. The mechanism may be related to the activation of NF-¦ÊB signaling pathway and the promotion of miR-21 expression which leads to the inhibition of GCLC expression and the significant decrease of intracellular reductive GSH synthesis.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Huang, Zeqian’s team published research in Chemical Engineering Journal (Amsterdam, Netherlands) in 2020-11-01 | CAS: 83730-53-4

Bone-targeted oxidative stress nanoamplifier for synergetic chemo/chemodynamic therapy of bone metastases through increasing generation and reducing elimination of ROS. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

The treatment of bone metastases remains an enormous challenge in clin. application. Strategies utilizing reactive oxygen species (ROS) to induce cell death show great potential for enhanced cancer therapy. Thus, for the first time, a versatile alendronate (ALN)-functionalized and cinnamaldehyde (CA)-loaded nanoscale coordination polymer (denoted as CA/ALN@FcB) based on 1,1¡ä-ferrocenedicarboxylicacid (Fc) and L-buthionine-sulfoximine (BSO) was properly fabricated as an oxidative stress nanoamplifier for synergetic chemo/chemodynamic therapy of bone metastases. With appropriate size and strong bone affinity of ALN, CA/ALN@FcB can preferentially accumulate in the bone metastatic site. In this nanoamplifier, CA can act as the ROS generator to produce ROS to damage cancer cells and boost intracellular hydrogen peroxide (H2O2) level, which can be converted into hydroxyl radical (?OH) with the catalysis of Fc via Fenton reaction. Simultaneously, glutathione (GSH) depletion mediated by BSO can inhibit ROS elimination to maintain H2O2 level and ?OH amount, ultimately leading to superior antitumor effect. Both in vitro and in vivo results demonstrated the self-enhanced synergetic chemo/chemodynamic therapy of CA/ALN@FcB. Such a nanoamplifier can generate and maintain sufficient ROS without the introduced external light triggering, exactly addressing the dilemma posed by fewer light penetration as well as the uncertain location of bone metastases. This study not only provides a novel strategy to achieve excellent cancer therapy by boosting ROS generation and simultaneously inhibiting ROS elimination, but also creates the precedent for the application of chemodynamic therapy for bone metastases treatment.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Xu, Qianhe’s team published research in Biochimica et Biophysica Acta, Molecular Cell Research in 2022-10-31 | CAS: 83730-53-4

Revealing PACMA 31 as a new chemical type TrxR inhibitor to promote cancer cell apoptosis. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Thioredoxin reductase (TrxR) is a pivotal regulator of redox homeostasis, while dysregulation of redox homeostasis is a hallmark for cancer cells. Thus, there is considerable potential to inhibit the aberrantly upregulated TrxR in cancer cells to discover selective cancer therapeutic agents. Nevertheless, the structural types of TrxR inhibitors presented currently are still relatively limited. We herein report that PACMA 31, previously reported to inhibit protein disulfide isomerase (PDI), is a potent TrxR inhibitor. PACMA 31 possesses a pharmacophore scaffold that is structurally different from the announced TrxR inhibitors and exhibits effective cytotoxicity against cervical cancer cells. Our results reveal that PACMA 31 selectively inhibits TrxR over the related glutathione reductase (GR) and in the presence of reduced glutathione (GSH). Further studies with mutant enzyme and mol. docking suggest that the propynamide fragment of PACMA 31 interacts covalently with the selenocysteine residue of TrxR. Moreover, PACMA 31 effectively and selectively curbs TrxR activity in cells and further stimulates the production of reactive oxygen species (ROS) at low micromolar concentrations, which in turn triggers the accumulation of oxidized thioredoxin (Trx) and GSSG in cells. Follow-up studies demonstrate that PACMA 31 targets TrxR in cells to induce oxidative stress-mediated cancer cell apoptosis. Our results provide a new structural type of TrxR inhibitor that may serve as a useful probe for investigating the biol. of TrxR-implicated pathways, and uncover a new target of PACMA 31 that contributes to it becoming a candidate for cancer treatment.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem

Romero, Rodrigo’s team published research in Nature Cancer in 2020-06-02 | CAS: 83730-53-4

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Approx. 20-30% of human lung adenocarcinomas (LUADs) harbor mutations in Kelch-like ECH-associated protein 1 (KEAP1) that hyperactivate the nuclear factor, erythroid 2-like 2 (NFE2L2) antioxidant program. We previously showed that Kras-driven Keap1-mutant LUAD is highly aggressive and dependent on glutaminolysis. Here we performed a druggable genome CRISPR screen and uncovered a Keap1-mutant-specific dependency on solute carrier family 33 member 1 (Slc33a1), as well as several functionally related genes associated with the unfolded protein response. Genetic and biochem. experiments using mouse and human Keap1-mutant tumor lines, as well as preclin. genetically engineered mouse models, validate Slc33a1 as a robust Keap1-mutant-specific dependency. Furthermore, unbiased genome-wide CRISPR screening identified addnl. genes related to Slc33a1 dependency. Overall, our study provides a rationale for stratification of patients harboring KEAP1-mutant or NRF2-hyperactivated tumors as likely responders to targeted SLC33A1 inhibition and underscores the value of integrating functional genetic approaches with genetically engineered mouse models to identify and validate genotype-specific therapeutic targets.

Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1. 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

Chen, Feng’s team published research in Dalton Transactions in 2022 | CAS: 83730-53-4

Effect of cysteine thiols on the catalytic and anticancer activity of Ru(II) sulfonyl-ethylenediamine complexes. Recommended basis is Sulfoximine, Bioisosteric. Products is: https://www.ambeed.com/products/50578-18-2.html, 145026-07-9

Authors have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1-8 of [(¦Ç6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-Ph or biphenyl (biph), X = Cl or I, and R1 is Ph, 4-Me-Ph, 4-NO2-Ph or dansyl. The ‘piano-stool’ structure of complex 3, [(¦Ç6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by x-ray crystallog. The values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1-8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50¦ÌM, although, remarkably, complex 7 [(¦Ç6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clin. drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5-9.7 h-1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(¦Ç6-biph)2Ru2(GS)3]2- or [(¦Ç6-biph)2Ru2(NAC-H)3]2-, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(¦Ç6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.

Referemce:
Benzoxazole – Wikipedia,
Benzoxazole | C7H5NO – PubChem