Indirubin

Structural formula
General
Surname	Indirubin
other names	Indigo red Indigo purpurine CI 75790 3- (1,3-Dihydro-3-oxo-2 H -indol-2-ylidene) -1,3-dihydro-2 H -indol-2-one 2,3-biindolinylidene-2 ​​', 3-dione
Molecular formula	C 16 H 10 N 2 O 2
Brief description	red solid
External identifiers / databases
CAS number 479-41-4 EC number 610-392-0 ECHA InfoCard 100.119.646 PubChem 5359405 ChemSpider 4514277 DrugBank DB12379 Wikidata Q1661452
properties
Molar mass	262.26 g · mol -1
Physical state	firmly
Melting point	> 430 ° C
solubility	soluble in ethanol , diethyl ether and acetone , insoluble in water, diluted acids and alkalis
safety instructions
GHS labeling of hazardous substances Caution H and P phrases H: 315-319-335 P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Indoxyl reactions

Indirubin , also Indigorot is a reddish violet dye and a structural isomer of indigo (blue) or isoindigo (brown-red).

Occurrence

Different species, for example Isatis tinctoria (woad), Indigofera tinctoria or some types of snail form natural precursors from which the three isomers or their derivatives arise. The indigoid compounds themselves do not occur in living organisms, but arise from the dead material through enzymatic or acidic hydrolysis under oxidative conditions. In addition to indigo, indirubin is also produced by the action of certain bacteria on the so-called metabolic indican or indoxyl sulfate, which can develop in large quantities in the urine of these patients as a result of impaired tryptophan breakdown in blue diaper syndrome (indicanuria) and cause the urine to turn purple or blue leads.

Some precursors, all of which are derivatives of indoxyl, are shown in the reaction scheme. Indoxyl derivatives with free hydroxyl groups and isatin derivatives appear as intermediate stages in the formation of indigoid dyes .

synthesis

Initially, indirubin was only a by-product of attempts to synthesize indigo. Adolf von Baeyer and Emmerling received indirubin in variable proportions in addition to indigo by heating isatin, phosphorus trichloride and acetic acid chloride in a sealed glass tube together with phosphorus and then working them up with water. For example, the reaction of 2-chloro-3 H -indol-3-one with ammonium sulfide or white phosphorus and subsequent aqueous work-up or with zinc dust in glacial acetic acid gave indirubin as a by-product.

For the first time, indirubin was specifically synthesized by Baeyer from an ethanolic indoxyl solution , isatin and sodium carbonate in 1881.

use

In natural indigo, the presence of a small and variable admixture of the red dye causes a variation in the shades of blue. However, pure indirubin has also been used to dye textiles. However, its use on a larger scale failed because of its poor color fastness.

As an effective component of natural indigo, it has also been used as a medicine for centuries , and in modern medicine it is used as an anticancer agent. Chronic myeloid leukemia (CML) was treated in China with Danggui Longhui Wan, which consists of ten herbal ingredients and musk . The antileukemic effect could be attributed to only one of the herbal ingredients, the Qingdai or Indigo naturalis. Furthermore, the anti-leukemic property could be ascribed to a single ingredient, the indirubin, which is contained in natural indigo in amounts between 0.05 and 0.3%. Indirubin has also been identified as an ingredient in dried plant material from Orchidaceae Calanthe discolor, which was used in traditional Chinese medicine to treat inflammation and bacterial infections. Although it shows only moderate effectiveness, its very low side effects compared to other antileukemic agents arouse interest in its mechanism of action, which seems to be different from all antileukemic active ingredients known to date.

Findings indicate that the antitumor effect of indirubin derivatives is based on a complex interaction of several sub-mechanisms, including intercalation and redox cycling , the main mechanism of action being the inhibition of enzymes that play a decisive role in the course of the cell division cycle, so-called CDKs or Cyclin-dependent kinases . For example, indirubin and some of its derivatives are inhibitors of the enzyme complex CDK1 / cyclin B.

history

Structural formula of Isatan B

The name indirubin first appeared in 1855. Isatan B , then still known as Indican , was isolated from the leaves of woad ( Isatis tinctoria ) and indirubin and indigo were obtained from them. Quote: "The latter substance ..." (indirubin) "... is always formed when the indican is decomposed by acids, but only after the indigo blue has developed and especially after prolonged boiling of the acidic liquid in which indigo blue was created from indican ". An X-ray structure analysis of the indirubin was published in 1961.

Individual evidence

1. ↑ ^{a b} W. Müller (Ed.): Handbuch der Farbenchemie. Basics, technology, applications . Ecomed Verlagsgesellschaft, 3rd supplement 2003, ISBN 3-609-72700-4 , p. 2. (Chapter 13.6)
2. ↑ ^{a b} entry on indirubin. In: Römpp Online . Georg Thieme Verlag, accessed on December 25, 2014.
3. ↑ There is not yet a harmonized classification for this substance . A labeling of 2H-indol-2-ones, 3- (1,3-dihydro-3-oxo-2H-indol-2-ylidene) -1,3-dihydro- in the Classification and derived from a self-classification by the distributor is shown Labeling Inventory of the European Chemicals Agency (ECHA), accessed on July 6, 2020.
4. ↑ A. Baeyer, A. Emmerling: Reduction of isatin to indig blue ... In: Chem. Ber. 1870, 3, pp. 514-517.
5. ↑ A. Baeyer: Synthesis of the indigo blue ... In: Chem. Ber. 1878, 11, pp. 1296-1297.
6. ↑ A. Baeyer: About the action of five-fold chlorophosphorus on isatin and related substances ... In: Chem. Ber. 1879, 12, pp. 456-461.
7. ↑ A. Baeyer: About the compounds of the indigo group ... In: Chem. Ber. 1881, 14, pp. 1741-1750.
8. ↑ Farbwerke formerly Meister Lucius & Brüning: Process for the representation of derivatives of the indirubins. Patent specification: DRP 283726, 1913.
9. ↑ Chinese Pharmacopoeia (1995) Vol. 1
10. ↑ C. Li, Y. Go, Z. Mao, K. Koyano, Y. Kai, N. Kanehisa, Q. Zhu, Z. Zhou, S. Wu: The Synthesis, Antileukemic Activitiy, and Crystal Structures of Indirubin Derivatives. .. In: Bull. Chem. Soc. Jpn. 1996, 69, pp. 1621-1627.
11. ^ ^{A b} W. Tang, G. Eisenbrand: Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. Springer, Heidelberg 1992, ISBN 0-387-19309-X .
12. ^ R. Han: Highlight on the Studies of Anticancer Drugs Derived from Plants in China ... In: Stem Cells . 1994, 12, pp. 53-63.
13. ↑ M. Yoshikawa, T. Murakami, A. Kishi, T. Sakurama, H. Matsuda, M. Nomura, H. Matsuda, M. Kubo: Novel indole S, O-bisdesmoside, calanthoside, the precursor glycoside of tryptanthrin, indirubin , and isatin, with increasing skin blood flow promoting effects, from two Calanthe species (Orchidaceae) ... In: Chemical and Pharmaceutical Bulletin . 1998, 46, pp. 886-888.
14. ↑ R. Hössel: Synthesis of derivatives of indirubin and investigations to elucidate the mechanism of their antineoplastic effect. Dissertation. University of Kaiserslautern, 1999.
15. ↑ R. Hössel et al .: Indirubin, the active constituent of a Chinese antileukemia medicine, inhibits cyclin-dependent kinases ... In: Nat. Cell Biol. 1999, 1, PMID 10559866 , pp. 60-67.
16. ↑ E. Schunk: Indigo. In: J. Liebig, H. Knopp (Ed.): Annual report on the progress of pure, pharmaceutical and technical chemistry, physics, mineralogy and geology. 1855, pp. 659-665.
17. ↑ PH Pandraud: Structure Cristalline de l'Indirubine. In: Acta Cryst. 14: 901-908 (1961).