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Osalmid (Oxaphenamide) Sale

(Synonyms: 羟苯水杨胺; Oxaphenamide; 4'-Hydroxysalicylanilide) 目录号 : GC32144

Osalmid suppresses ribonucleotide reductase (RNR) activity in a concentration-dependent manner, with a 50% RR activity-inhibitory concentration (IC50) of 8.23 μM.

Osalmid (Oxaphenamide) Chemical Structure

Cas No.:526-18-1

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10mM (in 1mL DMSO)
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实验参考方法

Cell experiment:

HepG2.2.15 cells are cultured in the presence of 200 μg/mL G418. Cell viability is determined using a Cell Counting Kit-8 in 96-well plates treated with Osalmid for designated times. For long term assays, the culture supernatants are replaced with fresh media containing Osalmid every two days. The control wells contained equivalent amounts of DMSO. The CC50 is calculated as the concentration of a compound that reduced the cell viability to 50% compared to the control[1].

Animal experiment:

Mice: The HBV-transgenic mouse lineage is initially produced on a BALB/c background. Osalmid or 3TC is suspended in 0.05% CMC-Na and administered once a day by gavage at 400 and 100 mg/kg, respectively, for 28 days. For the combination group, mice are intragastrically administered with a mixture of osalmid and 3TC. 0.05% CMC-Na solution is used as control. The mouse sera are collected and assayed for HBV DNA levels and AST/ALT activity. Mice are then sacrificed after the 28-day drug treatment and the livers are excised for analysis[1].

References:

[1]. Liu X, et al. Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein. Biochem Pharmacol. 2016 Mar 1;103:118-28.

产品描述

Osalmid suppresses ribonucleotide reductase (RNR) activity in a concentration-dependent manner, with a 50% RR activity-inhibitory concentration (IC50) of 8.23 μM.

Osalmid is shown to be 10-fold more active in inhibiting RR activity than hydroxyurea, and significantly inhibits HBV DNA and cccDNA synthesis in HepG2.2.15 cells. Osalmid significantly inhibits HBV DNA replication in a time- and dose-dependent manner[1].

Osalmid significantly reduces RR activity and HBV DNA replication in vivo[1].

[1] Liu X, et al. Biochem Pharmacol. 2016, 103:118-28.

Chemical Properties

Cas No. 526-18-1 SDF
别名 羟苯水杨胺; Oxaphenamide; 4'-Hydroxysalicylanilide
Canonical SMILES O=C(NC1=CC=C(O)C=C1)C2=CC=CC=C2O
分子式 C13H11NO3 分子量 229.23
溶解度 DMSO : ≥ 28 mg/mL (122.15 mM) 储存条件 Store at -20°C
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1 mM 4.3624 mL 21.8122 mL 43.6243 mL
5 mM 0.8725 mL 4.3624 mL 8.7249 mL
10 mM 0.4362 mL 2.1812 mL 4.3624 mL
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Research Update

Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer

Int J Radiat Oncol Biol Phys 2020 Dec 1;108(5):1368-1379.PMID:32763454DOI:10.1016/j.ijrobp.2020.07.2322.

Purpose: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC. Methods and materials: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and β-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo. Results: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs. Conclusions: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo.

Identification of Osalmid metabolic profile and active metabolites with anti-tumor activity in human hepatocellular carcinoma cells

Biomed Pharmacother 2020 Oct;130:110556.PMID:32763815DOI:10.1016/j.biopha.2020.110556.

Backgrounds: Ribonucleotide reductase (RR) catalyzes the essential step in the formation of all four deoxynucleotides. Upregulated activity of RR plays an active role in tumor progression. As the regulatory subunit of RR, ribonucleotide reductase subunit M2 (RRM2) is regarded as one of the effective therapeutic targets for DNA replication-dependent diseases, such as cancers. Recent studies have revealed that Osalmid significantly inhibits the activity of RRM2, but the metabolic profile of Osalmid remains unknown. Objective: The aim of this study was to clarify the metabolic profile including metabolites, isoenzymes and metabolic pathways of Osalmid. The anti-human hepatocellular carcinoma activity and mechanism of metabolites were further investigated. Materials and methods: Ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) was used for identifying metabolites and for characterizing phase I and phase II metabolic pathways with recombinant enzymes or in human liver microsomes of Osalmid. The eHiTS docking system was used for potential RRM2 inhibitor screening among metabolites. Cytotoxicity assays were performed for evaluating cell proliferation inhibitory activity of metabolites. Cell cycle assays and cell apoptosis assays were assessed by flow cytometry. Western blotting analysis of RRM2, cyclin D1, p21, p53, phosphorylated p53, Bcl-2 and Bax was performed to explore the anti-hepatocellular carcinoma mechanism of the active metabolites. Results: Ten metabolites of Osalmid were identified, and none of them have been reported previously. Hydroxylation, glucuronidation, sulfonation, acetylation and degradation were recognized as the main metabolic processes of Osalmid. Isozymes of CYP1A2, CYP2C9, UGT1A1, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 were involved in phase I and phase II metabolism of Osalmid. Metabolites M7, M8 and M10 showed higher binding affinities with the RRM2 active site than Osalmid. Metabolite M7 exhibited potent inhibitory activity to hepatocellular carcinoma cell lines by both competitive inhibition and down-regulation of RRM2. Moreover, M7 significantly induced cell cycle arrest and apoptosis by activating p53-related pathways. Conclusions: The metabolic profile of Osalmid was identified. M7 significantly inhibited human hepatocellular carcinoma progression by inhibiting RRM2 activity. Furthermore, M7 induced cell cycle arrest and apoptosis by activating p53-related signaling pathways.

Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein

Biochem Pharmacol 2016 Mar 1;103:118-28.PMID:26774458DOI:10.1016/j.bcp.2016.01.003.

Chronic hepatitis B virus (HBV) infection is a key factor for hepatocellular carcinoma worldwide. Ribonucleotide reductase (RR) regulates the deoxyribonucleoside triphosphates biosynthesis and serves as a target for anti-cancer therapy. Here, we demonstrate that RR is essential for HBV replication and the viral covalently-closed-circular DNA (cccDNA) synthesis in host liver cells. By performing computer-assisted virtual screening against the crystal structure of RR small subunit M2 (RRM2), Osalmid, was identified as a potential RRM2-targeting compound. Osalmid was shown to be 10-fold more active in inhibiting RR activity than hydroxyurea, and significantly inhibited HBV DNA and cccDNA synthesis in HepG2.2.15 cells. In contrast, hydroxyurea and the RR large subunit (RRM1)-inhibitory drug gemcitabine showed little selective activity against HBV replication. In addition, Osalmid also was shown to possess potent activity against a 3TC-resistant HBV strain, suggesting utility in treating drug-resistant HBV infections. Interestingly, Osalmid showed synergistic effects with lamivudine (3TC) in vitro and in vivo without significant toxicity, and was shown to inhibit RR activity in vivo, thus verifying its in vivo function. Furthermore, 4-cyclopropyl-2-fluoro-N-(4-hydroxyphenyl) benzamide (YZ51), a novel derivative of Osalmid, showed higher efficacy than Osalmid with more potent RR inhibitory activity. These results suggest that RRM2 might be targeted for HBV inhibition, and the RRM2-targeting compound Osalmid and its derivative YZ51 could be a novel class of anti-HBV candidates with potential use for hepatitis B and HBV-related HCC treatment.