MITHRAMYCIN A Chemical Properties

Melting point:

180-183 °C

alpha 

D20 -51° (c = 0.4 in ethanol)

Boiling point:

761.72°C (rough estimate)

Density 

1.1576 (rough estimate)

refractive index 

1.6500 (estimate)

storage temp. 

2-8°C

solubility 

Soluble in DMSO (up to 20 mg/ml) or in Ethanol (up to 10 mg/ml)

pka

4.54±0.60(Predicted)

form 

Powder

color 

Red to brown

Merck 

13,7619

BRN 

5236667

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 1 month.

EPA Substance Registry System

Plicamycin (18378-89-7)

Safety Information

Hazard Codes 

Xn,T+

Risk Statements 

22-26/27/28

Safety Statements 

45-38-36/37/39-28A-22

RIDADR 

3249

WGK Germany 

3

RTECS 

PZ2800000

F 

10

HazardClass 

6.1(b)

PackingGroup 

III

HS Code 

29419090

Hazardous Substances Data

18378-89-7(Hazardous Substances Data)

Toxicity

LD50 in mice, rats (mg/kg): 2.14, 1.74 i.v. (Slavik, Carter)

MSDS

• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS

MITHRAMYCIN A Usage And Synthesis

Description

Mithramycin is an antineoplastic antibiotic produced by Streptomyces plicatus. It is well known as the aureolic acid antitumor antibiotic that inhibits both cancer growth and bone resorption by cross-linking GC-rich DNA, thus blocking binding of Sp-family transcription factors to gene regulatory elements. Transcription of c-Src, a gene implicated in many human cancers and required for osteoclast-dependent bone resorption, is regulated by the binding of Sp factors to specific elements in its promoter. Therefore, this gene represents an important anticancer target and a potential lead target through which mithramycin displays action against osteoclastic bone resorption via an unknown mechanism. Hazards of handling this drug by the health-care personnel arise from a combination of factors: (1) its inherent toxicity and (2) the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (e.g., workers’ lunches), inhalation of drug dusts or droplets, or direct skin contact. Mithramycin has been used to decrease bone resorption in patients with humoral hypercalcemia and Paget’s disease.

Chemical Properties

yellow powder

Uses

Transcription inhibitor

Uses

Mithramycin was the first of the aureolic acid class of antitumour antibiotics, isolated from Streptomyces. Mithramycin inhibits transcription and protein synthesis by non-covalent binding with G-C-rich duplex DNA in the presence of magnesium and zinc ions. Mithramycin also induces differentiation of leukemic cells accompanied by an early decrease in c-myc expression, and selectively inhibits collagen-1 gene expression in human fibroblasts.

Uses

Mithramycin A was the first of the aureolic acid class of antitumor antibiotics, isolated from Streptomyces. Mithramycin inhibits transcription and protein synthesis by non-covalent binding with G-C-rich duplex DNA in the presence of magnesium and zinc ions. Mithramycin also induces differentiation of leukemic cells accompanied by an early decrease in c-myc expression, and selectively inhibits collagen-1 gene expression in human fibroblasts.

Indications

Plicamycin (mithramycin, Mithracin) is one of the chromomycin group of antibiotics produced by Streptomyces tanashiensis. Plicamycin binds to DNA and inhibits transcription. It also inhibits resorption of bone by osteoblasts, thus lowering serum calcium levels.Very little is known about its distribution, metabolism, and excretion. Because of its severe toxicity, plicamycin has limited clinical utility.The major indication for plicamycin therapy is in the treatment of life-threatening hypercalcemia associated with malignancy. Plicamycin also can be used in the palliative therapy of metastatic testicular carcinoma when all other known active drugs have failed.

Definition

ChEBI: Mithramycin is a carbohydrate-containing antibiotic, an anthracycline antibiotic, an aureolic acid and a secondary alpha-hydroxy ketone. It has a role as an antineoplastic agent, an EC 2.7.7.6 (RNA polymerase) inhibitor and a metabolite.

Application

Mithramycin, recently renamed plicamycin, was found in the culture broth of Streptomyces argillaceus and S. tanashiensis by Abbott Laboratories in 1952. It is structurally related to chromomycin A3. Mithramycin shows strong inhibitory activity against malignant cells of human origin. It acts by inhibition of the DNA-directed RNA synthesis through binding with DNA. Mithramycin is used intravenously to treat cancers of the embryonal cells, seminoma, choriocarcinoma, etc.

brand name

Mithracin (Pfizer) [Name previously used: Mithramycin.].

General Description

Chemical structure: aureolic acid

Biological Activity

Anticancer antibiotic that selectively binds to G-C-rich DNA in the presence of Mg 2+ or Zn 2+ , inhibiting RNA and DNA polymerase action. Inhibits c-myc expression and induces myeloid differentiation of HL-60 promyelocytic leukemia cells.

Biochem/physiol Actions

Anticancer antibiotic. Inhibits transcription and protein synthesis. Binds to DNA in native chromatin. Substrate of Pgp in MDR phenotypes.

storage

Store at -20°C

Purification Methods

Purify mithramycin A by crystallisation from CHCl3. It is soluble in MeOH, EtOH, Me2CO, EtOAc, Me2SO and H2O, and moderately soluble in CHCl3, but is slightly soluble in *C6H6 and Et2O. It is a fluorescent antitumour agent used in flow cytometry. [Thiem & Meyer Tetrahedron 37 551 1981, NMR: Yu et al. Nature 218 193 1968, Beilstein 17/1 V 672.]

Toxicity evaluation

Mithramycin inhibits mRNA and protein synthesis by adhering to DNA. Mithramycin appears to affect bone resorption by stimulating osteoclast activity and results in hypocalcemia and hypophosphatemia. It is believed to lower serum calcium concentrations, but the exact mechanism is unknown. It may act by blocking hypercalcemic action of vitamin D or by inhibiting the effect of parathyroid hormone on osteoclasts. Its inhibition of DNA-dependent RNA synthesis appears to render osteoclasts unable to fully respond to parathyroid hormone with the biosynthesis necessary for osteolysis.

References

1) Lin?et al. (2007),?Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells; Anticancer Drugs,?18?1157 2) Jia?et al.?(2010),?Combined treatment of pancreatic cancer cells with mithramycin A and tolfenamic acid promotes Sp1 degradation and synergistic anti-tumor activity; Cancer Res.,?70?1111 3) Lee?et al. (2006),?Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites; Mol. Cancer Ther.,?5?2737

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