Thiolutin

RNA polymerase inhibitor,antibiotic CAS# 87-11-6

Thiolutin

2D Structure

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Thiolutin

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Chemical Properties of Thiolutin

Cas No. 87-11-6 SDF Download SDF
PubChem ID 6870 Appearance Powder
Formula C8H8N2O2S2 M.Wt 228.28
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 5 mg/ml in DMSO
Chemical Name N-(4-methyl-5-oxodithiolo[4,3-b]pyrrol-6-yl)acetamide
SMILES CC(=O)NC1=C2C(=CSS2)N(C1=O)C
Standard InChIKey MHMRAFONCSQAIA-UHFFFAOYSA-N
Standard InChI InChI=1S/C8H8N2O2S2/c1-4(11)9-6-7-5(3-13-14-7)10(2)8(6)12/h3H,1-2H3,(H,9,11)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Thiolutin

DescriptionAntibiotic; inhibits bacterial RNA polymerase. Inhibits adhesion of HUVEC cells to vitronectin (IC50 = 0.83 mM) and subsequently reduces paxillin levels. Suppresses tumor cell-induced angiogenesis.

Thiolutin Dilution Calculator

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Preparing Stock Solutions of Thiolutin

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 4.3806 mL 21.9029 mL 43.8059 mL 87.6117 mL 109.5146 mL
5 mM 0.8761 mL 4.3806 mL 8.7612 mL 17.5223 mL 21.9029 mL
10 mM 0.4381 mL 2.1903 mL 4.3806 mL 8.7612 mL 10.9515 mL
50 mM 0.0876 mL 0.4381 mL 0.8761 mL 1.7522 mL 2.1903 mL
100 mM 0.0438 mL 0.219 mL 0.4381 mL 0.8761 mL 1.0951 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Thiolutin

Antibiotic; inhibits bacterial RNA polymerase. Inhibits adhesion of HUVEC cells to vitronectin (IC50 = 0.83 mM) and subsequently reduces paxillin levels. Suppresses tumor cell-induced angiogenesis.

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References on Thiolutin

Identification and characterization of the biosynthetic gene cluster of thiolutin, a tumor angiogenesis inhibitor, in Saccharothrix algeriensis NRRL B-24137.[Pubmed:25353334]

Anticancer Agents Med Chem. 2015;15(3):277-84.

In this study, a new dithiolopyrrolone biosynthetic pathway was identified in Saccharothrix algeriensis NRRL B-24137, which was reported to produce a variety of dithiolopyrrolone natural products including Thiolutin, a potential drug candidate for tumor angiogenesis inhibition. Bioinformatics analysis of the cluster revealed that it contains all the essential genes for holothin core biosynthesis and several other auxiliary genes. Interestingly, heterologous expression of the gene cluster in Streptomyces albus only induced the production of holomycin, implying that the gene responsible for the N4-methylation and the gene(s) involved in the formation of various acylated chains on N7 position of the holothin may locate outside the gene cluster. Incubation of holomycin with S-adenosyl-L-methionine (SAM) in the cell-free extract of Sa. algeriensis resulted in the production of Thiolutin, suggesting that the N4-methyl group of Thiolutin is originated from SAM, and the N4-methylation could be in the late stage of biosynthesis of Thiolutin type dithiolopyrrolones. An evolution-based model for biosynthesis of Thiolutin and its analogs was further proposed based on these results.

Comprehensive characterization of heat shock protein 27 phosphorylation in human endothelial cells stimulated by the microbial dithiole thiolutin.[Pubmed:18720982]

J Proteome Res. 2008 Oct;7(10):4384-95.

Thiolutin is a sulfur-based microbial compound with known activity as an angiogenesis inhibitor. Relative to previously studied angiogenesis inhibitors, Thiolutin is a remarkably potent inducer of heat shock protein 27 (Hsp27) phosphorylation. This phosphorylation requires p38 kinase but is independent of increased p38 phosphorylation. To elucidate how Thiolutin regulates Hsp27 phosphorylation and ultimately angiogenesis, Hsp27 was immunoprecipitated using nonphosphorylated and phospho-Ser78 specific antibodies from lysates of Thiolutin treated and untreated human umbilical vein endothelial cells and analyzed by LC-MS. Separate LC-MS analyses of Lys-C, Lys-C plus trypsin, and Lys-C plus Glu-C digests provided 100% sequence coverage, including the identification of a very large 13 kDa Lys-C fragment using a special sample handling procedure (4 M guanidine HCl) prior to the LC-MS analysis to improve the large peptide recovery. The analysis revealed a novel post-translational modification of Hsp27 involving truncation of the N-terminal Met and acetylation of the penultimate Thr. Analysis of a Glu-C fragment containing two phosphorylation sites, Ser78 and Ser82, and a tryptic fragment containing the other phosphorylation site, Ser15, enabled quantitative stoichiometry of Hsp27 phosphorylation by LC-MS. The strategy revealed details of Hsp27 phosphorylation, including significant di-phosphorylation at both Ser78 and Ser82, that would be difficult to obtain by traditional approaches because oligomerization of the hydrophobic N-terminal region of the molecule prevents efficient enzymatic cleavage. The combination of Western blotting, immunoprecipation, and LC-MS provides a quantitative analysis of Thiolutin-stimulated Hsp27 phosphorylation and further defines the role of Hsp27 in the antiangiogenic activities of Thiolutin and related dithiolethiones.

The transcriptional inhibitor thiolutin blocks mRNA degradation in yeast.[Pubmed:17914747]

Yeast. 2008 Feb;25(2):85-92.

Thiolutin is commonly used as a general inhibitor of transcription in yeast. It has been used to calculate mRNA decay rates by stopping the transcription and then determining the relative abundance of individual mRNAs at different times after inhibition. We report here that Thiolutin is also an inhibitor of mRNA degradation, and thus its use can lead to miscalculations of mRNA half-lives. The inhibition of mRNA decay seems to affect the mRNA degradation pathway without impeding poly(A) shortening, given that the decay rate of total poly(A) amount is not reduced by Thiolutin. Moreover, the Thiolutin-dependent inhibition of mRNA degradation has variable effects on different functional groups of genes, suggesting that they use various degradation pathways for their mRNAs.

Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton.[Pubmed:19579057]

Cell Stress Chaperones. 2010 Mar;15(2):165-81.

Thiolutin is a dithiole synthesized by Streptomyces sp. that inhibits endothelial cell adhesion and tumor growth. We show here that Thiolutin potently inhibits developmental angiogenesis in zebrafish and vascular outgrowth from tissue explants in 3D cultures. Thiolutin is a potent and selective inhibitor of endothelial cell adhesion accompanied by rapid induction of HSPB1 (Hsp27) phosphorylation. The inhibitory effects of Thiolutin on endothelial cell adhesion are transient, potentially due to a compensatory increase in Hsp27 protein levels. Accordingly, heat shock induction of Hsp27 limits the anti-adhesive activity of Thiolutin. Thiolutin treatment results in loss of actin stress fibers, increased cortical actin as cells retract, and decreased cellular F-actin. Mass spectrometric analysis of Hsp27 binding partners following immunoaffinity purification identified several regulatory components of the actin cytoskeleton that associate with Hsp27 in a Thiolutin-sensitive manner including several components of the Arp2/3 complex. Among these, ArpC1a is a direct binding partner of Hsp27. Thiolutin treatment induces peripheral localization of phosphorylated Hsp27 and Arp2/3. Hsp27 also associates with the intermediate filament components vimentin and nestin. Thiolutin treatment specifically ablates Hsp27 interaction with nestin and collapses nestin filaments. These results provide new mechanistic insights into regulation of cell adhesion and cytoskeletal dynamics by Hsp27.

Thiolutin, an inhibitor of HUVEC adhesion to vitronectin, reduces paxillin in HUVECs and suppresses tumor cell-induced angiogenesis.[Pubmed:11433393]

Int J Cancer. 2001 Aug 1;93(3):307-16.

Recent studies have shown that integrin alpha v beta 3, a receptor for vitronectin, plays an important role in tumor-induced angiogenesis and tumor growth and that antagonists of alpha v beta 3 inhibit angiogenic processes including endothelial cell adhesion and migration. On the other hand, most inhibitors of integrin alpha v beta 3 are peptide antagonists that include the Arg-Gly-Asp (RGD) motif. We therefore reasoned that non-peptide inhibitors of endothelial cell adhesion to vitronectin might be useful for inhibition of tumor angiogenesis in vivo. We screened for low-molecular-weight natural products able to inhibit adhesion of human umbilical vein endothelial cells (HUVECs) to vitronectin, and pyrrothine group compounds including aureothricin, thioaurin and Thiolutin were isolated from microbial culture broths. Of these compounds, Thiolutin inhibited adhesion of HUVECs to vitronectin the most effectively (IC(50), 0.83 microM). In vivo experiments showed that Thiolutin significantly suppressed angiogenesis induced by tumor cells (S-180), a pathological form of neovascularization, in a mouse dorsal air sac assay system. To explore the mechanism of inhibition of HUVEC adhesion to vitronectin by Thiolutin, we examined the effect of this agent on intracellular cell adhesion signaling. We found that the amount of paxillin in HUVECs was significantly reduced by Thiolutin treatment, while those of other focal adhesion proteins including vinculin and focal adhesion kinase (FAK) were not. Metabolic labeling experiments showed that Thiolutin enhanced degradation of paxillin in HUVECs. Protease inhibitors (MG115 and E64-D) decreased the rate of degradation of the paxillin induced by Thiolutin and partially restored Thiolutin-induced inhibition of HUVEC adhesion to vitronectin. Based on these findings, we concluded that Thiolutin, an inhibitor of HUVEC adhesion to vitronectin, reduces the paxillin level in HUVECs and suppresses tumor cell-induced angiogenesis in vivo.

RNA polymerase inhibitors with activity against rifampin-resistant mutants of Staphylococcus aureus.[Pubmed:11036042]

Antimicrob Agents Chemother. 2000 Nov;44(11):3163-6.

A collection of rifampin-resistant mutants of Staphylococcus aureus with characterized RNA polymerase beta-subunit (rpoB) gene mutations was cross-screened against a number of other RNA polymerase inhibitors to correlate susceptibility with specific rpoB genotypes. The rpoB mutants were cross-resistant to streptolydigin and sorangicin A. In contrast, Thiolutin, holomycin, corallopyronin A, and ripostatin A retained activity against the rpoB mutants. The second group of inhibitors may be of interest as drug development candidates.

Mode of action of thiolutin, an inhibitor of macromolecular synthesis in Saccharomyces cerevisiae.[Pubmed:4597739]

Antimicrob Agents Chemother. 1973 Jun;3(6):729-38.

The sulfur-containing antibiotic Thiolutin has been shown to be a potent, reversible inhibitor of the growth of Saccharomyces cerevisiae. Viability was unaffected over the concentration range of 4 to 100 mug/ml. At concentrations as low as 2 mug/ml, the drug inhibited ribonucleic acid (RNA) and protein synthesis in whole cells and spheroplasts. At these low concentrations, protein synthesis continued for a short period of time after RNA synthesis was completely stopped. With higher drug concentrations (greater than 20 mug/ml) protein synthesis was inhibited; concentrations of Thiolutin up to 100 mug/ml did not affect translocation or peptide bond formation in cell-free protein-synthesizing systems from yeast. The effect of Thiolutin on the activity of partially purified deoxyribonucleic acid-dependent RNA polymerases was examined, and the drug was found to be a potent inhibitor of RNA synthesis in vitro. Inhibition was greatest when the polymerase was preincubated with Thiolutin. Several mechanisms are discussed to explain the multiple effects of Thiolutin on S. cerevisiae. Since the action of the drug is easily reversed, Thiolutin may prove to be of use in studies of various stages of yeast growth.

Description

Thiolutin (Acetopyrrothin) is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Thiolutin inhibits the JAMM metalloproteases Csn5, Associated-molecule-with-the-SH3-Domain-of-STAM (AMSH) and Brcc36. Thiolutin is a potent and selective inhibitor of endothelial cell adhesion accompanied by rapid induction of Heat-shock protein beta-1 (Hsp27) phosphorylation.

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