Mithramycin AAnticancer antibiotic CAS# 18378-89-7 |
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Quality Control & MSDS
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Chemical structure
3D structure
Cas No. | 18378-89-7 | SDF | Download SDF |
PubChem ID | 29051 | Appearance | Powder |
Formula | C52H76O24 | M.Wt | 1085.16 |
Type of Compound | N/A | Storage | Desiccate at -20°C |
Synonyms | Plicamycin,NSC 24559,PA 144 | ||
Solubility | DMSO : ≥ 100 mg/mL (92.15 mM) *"≥" means soluble, but saturation unknown. | ||
Chemical Name | (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5R,6R)-4-[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-8,9-dihydroxy-7-methyl-3,4-dihydro-2H-anthracen-1-one | ||
SMILES | CC1C(C(CC(O1)OC2CC(OC(C2O)C)OC3=CC4=CC5=C(C(=O)C(C(C5)C(C(=O)C(C(C)O)O)OC)OC6CC(C(C(O6)C)O)OC7CC(C(C(O7)C)O)OC8CC(C(C(O8)C)O)(C)O)C(=C4C(=C3C)O)O)O)O | ||
Standard InChIKey | CFCUWKMKBJTWLW-WZIVUMCRSA-N | ||
Standard InChI | InChI=1S/C52H76O24/c1-18-29(72-34-14-30(43(58)21(4)68-34)73-33-13-28(54)42(57)20(3)67-33)12-26-10-25-11-27(49(66-9)48(63)41(56)19(2)53)50(47(62)39(25)46(61)38(26)40(18)55)76-36-16-31(44(59)23(6)70-36)74-35-15-32(45(60)22(5)69-35)75-37-17-52(8,65)51(64)24(7)71-37/h10,12,19-24,27-28,30-37,41-45,49-51,53-61,64-65H,11,13-17H2,1-9H3/t19-,20-,21-,22-,23-,24-,27+,28-,30-,31-,32-,33+,34+,35+,36+,37+,41+,42-,43-,44-,45-,49+,50+,51-,52+/m1/s1 | ||
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. |
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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. |
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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. |
Description | Anticancer antibiotic that selectively binds to G-C-rich DNA in the presence of Mg2+ or Zn2+, inhibiting RNA and DNA polymerase action. Inhibits c-myc expression and induces myeloid differentiation of HL-60 promyelocytic leukemia cells. |
Mithramycin A Dilution Calculator
Mithramycin A Molarity Calculator
1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
1 mM | 0.9215 mL | 4.6076 mL | 9.2152 mL | 18.4305 mL | 23.0381 mL |
5 mM | 0.1843 mL | 0.9215 mL | 1.843 mL | 3.6861 mL | 4.6076 mL |
10 mM | 0.0922 mL | 0.4608 mL | 0.9215 mL | 1.843 mL | 2.3038 mL |
50 mM | 0.0184 mL | 0.0922 mL | 0.1843 mL | 0.3686 mL | 0.4608 mL |
100 mM | 0.0092 mL | 0.0461 mL | 0.0922 mL | 0.1843 mL | 0.2304 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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Mithramycin A is a DNA-binding, anti-tumor and neuroprotective antibiotic originally isolated from S. grieseus that has long been used as a chemotherapeutic agent. It mediates its protective function, in part, by regulating acetylation of histones or transcription factors and, thereby, chromatin accessibility to transcriptional machinery. As a selective Sp1 inhibitor, mithramycin A binds to GC rich DNA sequences, displacing Sp1 transcription factor binding to oncogene promoters, which inhibits their expression. Mithramycin A (at 10-200 nM) can sensitize tumor cells to TRAIL-induced apoptosis and has been used to selectively target tumor cells in many different cancer models.
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Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.[Pubmed:27072684]
Neurochem Res. 2016 Aug;41(8):1924-38.
Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of Mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Abeta levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Abeta production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3beta signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.
Structures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1.[Pubmed:27587584]
Nucleic Acids Res. 2016 Oct 14;44(18):8990-9004.
Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS-FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS-FLI1. We report a crystal structure of an MTM analogue MTM SA-Trp bound to a DNA oligomer containing a site GGCC, and two structures of a novel analogue MTM SA-Phe in complex with DNA. MTM SA-Phe is bound to sites AGGG and GGGT on one DNA, and to AGGG and GGGA(T) (a FLI1 binding site) on the other, revealing how MTM recognizes different DNA sequences. Unexpectedly, at sub-micromolar concentrations MTMs stabilize FLI1-DNA complex on GGAA repeats, which are critical for the oncogenic function of EWS-FLI1. We also directly demonstrate by nuclear magnetic resonance formation of a ternary FLI1-DNA-MTM complex on a single GGAA FLI1/MTM binding site. These biochemical and structural data and a new FLI1-DNA structure suggest that MTM binds the minor groove and perturbs FLI1 bound nearby in the major groove. This ternary complex model may lead to development of novel MTM analogues that selectively target EWS-FLI1 or other oncogenic transcription factors, as anti-cancer therapeutics.
Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma.[Pubmed:27105533]
Oncotarget. 2016 May 24;7(21):30935-50.
Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPalpha. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFkappaB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.
Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor.[Pubmed:26979396]
Clin Cancer Res. 2016 Aug 15;22(16):4105-18.
PURPOSE: The goal of this study was to identify second-generation Mithramycin Analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established Mithramycin As an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients. EXPERIMENTAL DESIGN: We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time-lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma. RESULTS: EC-8105 was found to be the most potent analogue and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo CONCLUSIONS: These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic. Clin Cancer Res; 22(16); 4105-18. (c)2016 AACR.
Mithramycin cannot bind to left-handed poly(dG-m5dC) in the presence of Mg2+ ion.[Pubmed:1828342]
Biochem Biophys Res Commun. 1991 May 31;177(1):511-7.
Mithramycin (MTR) is an antitumor compound that inhibits RNA and DNA polymerase action by forming a non covalent complex with double strand DNA, in the presence of divalent cations. We have shown that in the presence of Mg2+, MTR binds to right-handed poly(dG-m5dC) as a dimer in the right-handed screwness conformation but cannot bind to left-handed poly(dG-m5dC).
Mithramycin selectively inhibits the transcriptional activity of a transfected human c-myc gene.[Pubmed:2147360]
Am J Med Sci. 1990 Oct;300(4):203-8.
The G-C specific DNA binding drug mithramycin selectively inhibits expression of the c-myc gene in a number of cell types. We have tested the ability of this agent to inhibit the expression of a transfected human c-myc gene in a murine fibroblast cell line. Expression of c-myc is inhibited in the first 24 hours of mithramycin exposure (in contrast to actin gene expression, which is unaffected). Nuclear runon transcription of c-myc by nuclei isolated from mithramycin treated cells is decreased, indicating inhibition of transcription initiation. However, treatment of isolated nuclei with Mithramycin Also results in decreased c-myc transcription. Thus, inhibition of c-myc expression by mithramycin in these cells appears to occur at the transcriptional level and is most likely mediated at both the transcription initiation and elongation level. This suggests that mithramycin selectively interacts with the G-C rich c-myc promoter, preventing formation of the c-myc transcription initiation complex.
Mithramycin selectively inhibits transcription of G-C containing DNA.[Pubmed:2962490]
Am J Med Sci. 1987 Nov;294(5):388-94.
Mithramycin induces a reversible inhibition of cellular RNA synthesis without affecting DNA synthesis. The authors have shown this drug induces myeloid differentiation of HL-60 promyelocytic leukemia cells and is an effective agent in certain patients with chronic granulocytic leukemia. In order to investigate the mechanism by which this drug inhibits RNA synthesis we have compared the effect of mithramycin on RNA synthesis by whole cells, isolated nuclei, and RNA synthesis by isolated E. coli RNA polymerase and eukaryotic RNA polymerase II. Exposure of HL-60 cells to Mithramycin At concentrations of 4.6 X 10(-7) m or higher for 48 hours causes an almost immediate inhibition of RNA synthesis (up to 85% at 4 hours) with only modest cytotoxicity at these concentrations. Endogenous RNA synthesis by isolated nuclei can be inhibited by mithramycin only at high concentrations (greater than 10(-5) m), suggesting that mithramycin primarily may inhibit initiation, rather than elongation. Mithramycin inhibits in vitro transcription of salmon sperm DNA by E. coli RNA polymerase at DNA:drug ratios similar to those required for RNA synthesis inhibition in whole cells. Similar DNA binding studies with synthetic oligonucleotides demonstrate that mithramycin is a potent inhibitor of transcription of Poly dG.dC by E. coli RNA polymerase but has no effect on transcription of Poly dA.dT. The rapid inhibition of whole cell and isolated RNA polymerase transcription, and the relative insensitivity of isolated nuclei, suggest mithramycin may interact with specific DNA sequences in order to inhibit the initiation of RNA synthesis in intact cells.