3-methylcholanthrene

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Structural formula
Structural formula of 3-methylcholanthrene
General
Surname 3-methylcholanthrene
other names
  • 20-methylcholanthrene
  • 3-MC
  • Dihydromethylbenz [ j ] aceanthrylene
  • 1,2-dihydro-3-methyl-benz [ j ] aceanthrylene
  • 3-methyl-1,2-dihydrocyclopenta [ ij ] tetraphene
Molecular formula C 21 H 16
Brief description

yellowish crystals

External identifiers / databases
CAS number 56-49-5
EC number 200-276-4
ECHA InfoCard 100,000,252
PubChem 1674
Wikidata Q223099
properties
Molar mass 268.35 g · mol -1
Physical state

firmly

density

1.28 g cm −3 (20 ° C)

Melting point

180  ° C

boiling point

280 ° C at 107 h Pa

solubility

practically insoluble in water

safety instructions
GHS labeling of hazardous substances
08 - Dangerous to health

danger

H and P phrases H: 350-413
P: 201-308 + 313
MAK

not classified, as a suspected carcinogenic effect

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

3-methylcholanthrene often with 3-MC abbreviated after the steroid - nomenclature as 20-methylcholanthrene referred to is a polycyclic aromatic hydrocarbon . The main body of the compound is cholanthrene . 3-methylcholanthrene is very carcinogenic . It is used in oncology as a carcinogen to trigger tumors in model organisms .

It was synthesized by James Wilfred Cook in 1934 and found to be highly carcinogenic.

Use and properties

Due to its strong carcinogenic effect, there is no technical application for 3-methylcholanthrene. In oncology it is a standard carcinogen that is frequently used to produce malignant tumors in model organisms . 3-methylcholanthrene is a more potent carcinogen than benzo [ a ] pyrene . 3-methylcholanthrene is mutagenic in bacteria and leads to chromosome breakage in the bone marrow (clastogenic effect). In animal experiments it induces the formation of DNA adducts .

In order to generate tumors, the test animals are given 3-methylcholanthrene either by brushing on the skin ( transdermal ) or injected under the skin ( subcutaneous ) or administered with food ( orally ) or injected into the abdominal cavity ( intraperitoneal ). The animals treated in this way usually develop different types of cancer , depending on the location of the application .

In its application to the skin develop in mice quickly carcinomas . Subcutaneous injection leads to sarcomas in mice and rats . Oral administration in a sesame oil dilution induces breast cancer in female rats . If the ovaries are removed beforehand , the risk of breast cancer drops significantly.

In addition, 3-methylcholanthrene influences folliculogenesis , the estrogen balance, the sexual cycle and the morphology of the sperm cells of the test animals.

3-methylcholanthrene activates the aryl hydrocarbon receptor . The activation of the Ah receptor in turn causes an interruption of the estradiol signal path. In some cells 3-MC acts as an activator of the estrogen receptors ER-α and ER-β, while in other cells it acts as a suppressor. The mode of action depends on whether the respective cell is able to metabolize 3-MC.

Depending on the organ and the enzymes present there , 3-MC is metabolized differently. The metabolites found in the liver include 1- or 2-hydroxy-, cis- and trans -1,2-dihydroxy-, 11,12-dihydroxy-11,12-dihydo-, and 1- and 2-keto- 3-methylcholanthrene.

3-methylcholanthrene is highly hydrophobic. The octanol-water partition coefficient (log K) is 6.42. The absorption maximum in ethanol is 359 nm.

Discovery and synthesis

The pyrolysis of deoxycholic acid leads to 3-methylcholanthrene

3-methylcholanthrene was first discovered by the two German chemists Heinrich Otto Wieland and Elisabeth Dane in 1933. The two received the compound as a decomposition product of deoxycholic acid , a sterol from the steroid family. The return of deoxycholic acid to the basic structure of a pure hydrocarbon provided structural evidence for deoxycholic acid.

The first synthesis of 3-methylcholanthrene took place in 1935 by the two Americans Louis Frederick Fieser and Arnold M. Seligman . They used the Elbs reaction .

JW Cook and GAD Haslewood recognized the carcinogenic potential of 3-methylcholanthrene shortly after its discovery by Wieland and Dane.

In 1936, in his book Chemistry of Natural Products Related to Phenanthrene , Fieser postulated that many cancers have their origin in 3-MC and related compounds that occur in the body as a metabolic product - for example of sex hormones or cholesterol. This thesis is no longer tenable in this form today.

Several more elegant synthetic routes for the preparation of 3-methylcholantrene are described in the literature. For example, a lactone can be obtained from 4-methylindanone and N , N- diethyl-1-naphthamide , which leads to 3-MC after a total of four stages. The overall yield is around 20%.

An alternative synthesis is via 5 -methylhomophthalic anhydride, which is reacted with 1-naphthamide lithiated in the 2-position . This route takes five steps and has a yield of approximately 55%.

3-methylcholanthrene may also be in the pyrolysis of cholesterol - derivatives form.

literature

  • P. Sims and PL Grover: Polycyclic Hydrocarbons and Cancer. HV Gelboin u. a. (Editors), Academic Press, 1981.
  • ET Bloom: Quantitative detection of cytetexic antibodies against tumors-specific antigens of murine sarcomas induced by 3-methylcholanthrene. In: J Natl Cancer Inst 44, 1970, p. 443, PMID 5523193 .
  • JD Kamp and HG Neumann: Absorption of carcinogens into the thoracic duct lymph of the rat: aminostilbene derivatives and 3-methylcholanthrene. In: Xenobiotica 5, 1975, pp. 717-727.
  • E. Bergmann and O. Blum-Bergmann: Synthesis of Methylcholanthrene. In: JACS 59, 1937, pp. 1573-1575. doi : 10.1021 / ja01287a502
  • LW Law and M. Lewisohn: Comparative Carcinogenicity of Some Cholanthrene Derivatives. (PDF; 358 kB) In: Cancer Research 1941, pp. 695-698.
  • MJ Shear: Studies in Carcinogenesis. III. Isomers of Cholanthrene and Methylcholanthrene. In: Am J Cancer 28, 1936, pp. 334-344.

Individual evidence

  1. ↑ a b c d e f g h Entry on 3-methylcholanthrene in the GESTIS substance database of the IFA , accessed on February 10, 2017(JavaScript required) .
  2. ↑ RTO Turner et al .: The role of complement in 3-methylcholanthrene-induced tumor formation. In: Molecular Immunology 44, 2007, pp. 3950-3951. doi : 10.1016 / j.molimm.2007.06.099 .
  3. ↑ DL Anger et al .: Spontaneous appearance of uterine tumors in vehicle and 3-methylcholanthrene-treated Wistar rats. In: Reprod Toxicol 22, 2006, pp. 760-764. PMID 16945501 .
  4. ↑ a b M. M. Coombs and TS Bhatt: Cyclopenta (a) phenanthrenes. CUP Archive, 1987, p. 6. ISBN 0-521-30123-8 .
  5. ↑ BH Rihn include: genotoxicity of 3-methylcholanthrene in liver of transgenic mice Big Blue. In: Environ Mol Mutagen 36, 2000, pp. 266-273.
  6. ↑ P. Bofetta et al.: Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. In: Cancer Causes & Control 8, 1997, pp. 444-472, PMID 9498904 (review article).
  7. ^ J. Doull et al. (Editors): Casarett and Doull's Toxicology. 3rd Edition, New York, Macmillan Co., Inc., 1986, p. 107.
  8. ^ CE Searle (Editor): Chemical Carcinogens. ACS Monograph 173, Washington, American Chemical Society, 1976, p. 73.
  9. ↑ M. Konstandi et al.: Modification of reproductive function in the rat by 3-methylcholanthrene. In: Pharmacol Res 35, 1997, pp. 107-111, PMID 9175578 .
  10. ^ AJ Wyrobek and WR Bruce: Chemical induction of sperm abnormalities in mice. In: PNAS 72, 1975, pp. 4425-4429, PMID 1060122 .
  11. ↑ SM Borman et al .: Ovotoxicity in female Fischer rats and B6 mice induced by low-dose exposure to three polycylic aromatic hydrocarbons: comparison through calculation of an ovotoxic index. In: Toxicol Appl Pharmacol 167, 2000, pp. 248-254, PMID 10986010 .
  12. ↑ DL Anger et al .: Spontaneous appearance of uterine tumors in vehicle and 3-methylcholanthrene-treated Wistar rats. In: Reproductive Toxicology 22, 2006, pp. 760-764, PMID 16945501 .
  13. ^ E. Swedenborg: 3-Methylcholanthrene displays dual effects on estrogen receptor (ER) alpha and ER beta signaling in a cell-type specific fashion. In: Mol Pharmacol 73, 2008, pp. 575-586, PMID 18003862 .
  14. ^ SR Myers and JW Flesher: Metabolism of the carcinogen 3-methylcholanthrene in human bone marrow preparations. In: Drug Metab Dispos 18, 1990, pp. 664-669, PMID 1981717 .
  15. ^ MG Shou and SK Yang: Metabolism of 2S-hydroxy-3-methylcholanthrene by rat liver microsomes. In: Carcinogenesis 11, 1990, pp. 2037-2045, PMID 2225338 .
  16. ^ GD Clayton and FE Clayton (editors): Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. third edition, John Wiley Sons, 1981-1982. P. 3367.
  17. ↑ C. Hansch and A. Leo: Substituent Constants for Correlation Analysis in Chemistry and Biology. New York, John Wiley and Sons, 1979.
  18. ↑ RC Weast (editor): Handbook of Chemistry and Physics. 60th Edition, CRC Press Inc., 1979, pp. C-245.
  19. ↑ H. Wieland and E. Dane: In: Z physiol Chem 219, 1933, p. 240.
  20. ↑ LF Fieser and AM Seligman: The Synthesis of Methylcholanthrene. In: JACS 57, 1935, pp. 228-229, doi : 10.1021 / ja01304a508
  21. ↑ LF Fieser and AM Seligman: The Synthesis of Methylcholanthrene. In: JACS 57, 1935, pp. 942-946, doi : 10.1021 / ja01308a050 .
  22. ↑ LF Fieser and AM Seligman: An Improved Method for the Synthetic Preparation of Methylcholanthrene. In: JACS 58, 1936, pp. 2482-2487, doi : 10.1021 / ja01303a037 .
  23. ↑ LF Fieser and EB Hershberg: Reduction and Hydrogenation of Methylcholanthrene. In: JACS 60, 1938, pp. 940-946, doi : 10.1021 / ja01271a054 .
  24. ↑ JW Cook and GAD Haslewood: The conversion of a bile acid into a hydrocarbon derived from 1: 2-benzanthracene. In: J Chem Soc 428, 1933, pp. 758-759.
  25. ↑ JW Cook and GAD Haslewood: The Synthesis of 5: 6-Dimethyl-1: 2-benzanthraquinone, a Degradation Product of Deoxycholic Acid. In: J Chem Soc 1934, pp. 428-433.
  26. ↑ JW Cook et al: Chemical Compounds as Carcinogenic Agents. In: Am J Cancer 29, 1937, pp. 219-259.
  27. ^ SA Jacobs and RG Harvey: Synthesis of 3-methylcholanthrene. In: Tetrahedron letters 22, 1981, pp. 1093-1096.
  28. ↑ T. Gimisis and M. Koreeda: A highly efficient synthesis of 3-methylcholanthrene. In: J Org Chem 58, 1993, pp. 7158-7161, doi : 10.1021 / jo00077a045 .
  29. ↑ Merck Index, 10th Edition, 1983, p. 867.