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Purity: ≥98%
OSMI-1 (OSMI1; OSMI 1) is a novel, potent, cell permeable and quinolinone-6-sulfonamide-based inhibitor of O-GlcNAc transferase (OGT) with an IC50 value of 2.7 μM. OSMI-1 induces a mass shift of nucleoporin62 (Nup62) that corresponds to the loss of O-GlcNAc residues and decreases levels of cellular O-GlcNAcase.
| Targets |
O-GlcNAc transferase (IC50 = 2.7 μM)
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| ln Vitro |
After treatment for 24 hours, OSMI-1 (50 μM; CHO cells) decreases viability by about 50% [1]. Treatment with OSMI-1 (10-100 μM; 24 hours; CHO cells) decreased O-GlcNAcylation (global O-linked N-acetylglucosamine) in a dose-dependent manner. OGT activity in cells is inhibited by OSMI-1 [1].
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| ln Vivo |
Mammals and zebrafish share remarkably comparable toxicity profiles; in fact, zebrafish are frequently used as a transitional species between conventional animal testing and cell-based evaluations. The in vivo acute toxicity of OSM1-1 was investigated using a zebrafish model. The LC50 values for OSM1-1 in the zebrafish model are 0.031 mg/mL (56 μM, 12 hours) and 0.025 mg/mL (45 μM, 24 hours) [2].
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| Enzyme Assay |
OGT activity assay[2]
HPLC was used to preliminarily analyze the inhibition of OGT by the compounds. According to the previously described41, the reaction condition was optimized. 200 μM CKII, 300 nM OGT, 1 mM UDP-GlcNAc, the compounds (100 μM) and buffer (150 mM NaCl, 1 mM EDTA, 2.5 mM tris(hydroxypropyl)phosphine, 25 mM Tris-HCl, pH 7.4) were mixed and incubated at room temperature for 1 h. After being precipitated by methanol, the reaction mixtures were loaded onto HPLC (the reverse-phase chromatographic column was Zorbax SB-C18 StableBond analytical column, 250 mm × 4.6 mm, and a Zorbax SB-C18 analytical guard column, 4.6 mm × 12.5 mm, 5 μm) to quantify the yield of glycopeptide product. Mobile phase A consisted of 0.1% TFA in H2O, and mobile phase B consisted of 0.1% TFA in MeCN. The components were eluted using a gradient (flow rate at 1 mL/min; at 0 min elution solvent mixture A/B = 90/10; at 20 min elution solvent mixture A/B = 70/30; wavelength = 214 nm). IC50 values were calculated using GraphPad 5 (n = 3).[2] A cell-free reaction system was used to determine the inhibition of O-GlcNAc level on a purified protein acceptor Nup62. Reaction mixtures containing 10 μM Nup62, 1 mM UDP-GlcNAc, 500 nM OGT, buffer (150 mM NaCl, 1 mM EDTA, 2.5 mM tris(hydroxypropyl)phosphine, 25 mM Tris-HCl, pH 7.4), and compounds were incubated at 37 °C for 1 h. Then, SDS-PAGE loading buffer was added and western blots were used to detect O-GlcNAc on Nup62.[2] OGT activity assay based on a UDP-Glo assay kit was performed as previously described10. Following the manufacturer’s protocol, assays were optimized and performed in white, flat bottom 384-well assay plate. CKII peptide was used as the acceptor. Reactions contained the following components: 250 nM OGT, 125 μM CKII and 40 μM UDP-GlcNAc, and buffer (150 mM NaCl, 1 mM EDTA, 2.5 mM tris(hydroxypropyl)phosphine, 25 mM Tris-HCl, pH 7.4). Luminescence was measured in triplicate using a microplate luminometer. IC50 values were calculated using GraphPad 5.[2] |
| Cell Assay |
Cell viability assay [1]
Cell Types: CHO Cell Tested Concentrations: 50 μM Incubation Duration: 24 hrs (hours) Experimental Results: Viability diminished by approximately 50% after 24 hrs (hours). Western Blot Analysis[1] Cell Types: CHO Cells Tested Concentrations: 10 μM, 25 μM, 50 μM, 100 μM Incubation Duration: 24 hrs (hours) Experimental Results: Overall OGlcNAc acylation was diminished in a dose-dependent manner. |
| Animal Protocol |
Acute toxicity assay[2]
All procedures of the animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee at the School of Life Science & Medicine, Dalian University of Technology and all experiments were conducted according to the relevant guidelines. Zebrafish embryos at 72-hours post-fertilization were selected for the acute toxicity assay. Zebrafish embryos were generated by natural pairwise mating and raised at 28.5 °C in embryo water. Zebrafish embryos were arrayed in 24-well plate (20 larvae per well) and incubated with 1 mL of embryo water per well containing various concentrations of L01 or OSMI-1 at 28.5 °C for 24 h. DMSO (0.1%, v/v) solution served as the control. The observation of zebrafish was made directly in the 24-well plate using an inverted dissecting microscope. The number of dead zebrafish in each concentration solution was recorded within 24 h, and the survival rate was calculated (%). |
| References | |
| Additional Infomation |
OSMI-1 is a sulfonamide resulting from the formal condensation of the sulfonic acid group of 2-oxo-1,2-dihydroquinoline-6-sulfonic acid with the primary amino group of (2R)-2-amino-N-(2-furylmethyl)-2-(2-methoxyphenyl)-N-(2-thienylmethyl)acetamide. OSMI-1 is a cell permeable inhibitor of O-linked beta-N-acetylglucosamine transferase (O-GlcNAc transferase, OGT). It has a role as an EC 2.* (transferase) inhibitor and an EC 2.4.1.255 (protein O-GlcNAc transferase) inhibitor. It is a sulfonamide, a member of quinolines, a member of furans, a member of thiophenes, an aromatic ether and a tertiary carboxamide.
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| Exact Mass |
563.118
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| Elemental Analysis |
C, 59.67; H, 4.47; N, 7.46; O, 17.03; S, 11.38
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| CAS # |
1681056-61-0
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| Related CAS # |
(Rac)-OSMI-1;2748153-92-4
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| PubChem CID |
118634407
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| Appearance |
White to light yellow solid
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.652
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| LogP |
4.32
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
39
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| Complexity |
1000
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| Defined Atom Stereocenter Count |
1
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| SMILES |
COC1=CC=CC=C1[C@H](C(=O)N(CC2=CC=CO2)CC3=CC=CS3)NS(=O)(=O)C4=CC5=C(C=C4)NC(=O)C=C5
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| InChi Key |
IYIGLWQQAMROOF-HHHXNRCGSA-N
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| InChi Code |
InChI=1S/C28H25N3O6S2/c1-36-25-9-3-2-8-23(25)27(28(33)31(17-20-6-4-14-37-20)18-21-7-5-15-38-21)30-39(34,35)22-11-12-24-19(16-22)10-13-26(32)29-24/h2-16,27,30H,17-18H2,1H3,(H,29,32)/t27-/m1/s1
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| Chemical Name |
(R)-N-(Furan-2-ylmethyl)-2-(2-methoxyphenyl)-2-(2-oxo-1,2-dihydroquinoline-6-sulfonamido)-N-(thiophen-2-ylmethyl)acetamide
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| Synonyms |
OSMI1 OSMI 1 OSMI-1
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~177.42 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (3.69 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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