479-41-4

Basic information

• Product Name: Indirubin
• Synonyms: [2,3'-Biindolinylidene]-2',3-dione;Indirubin (Synthetic), >=98%;Indirubin/Folium Isatidis Extract;Isoindogotin;(delta(sup2,3’)-biindoline)-2’,3-dione;3-(1,3-dihydro-3-oxo-2h-indol-2-ylidene)-1,3-dihydro-2h-indol-2-on;c.i.73200;2-(2-oxo-1h-indol-3-ylidene)-1h-indol-3-one
• CAS NO: 479-41-4
• Molecular Formula: C₁₆H₁₀N₂O₂
• Molecular Weight: 262.26
• EINECS: 1806241-263-5
• Product Categories: Inhibitors;Active Pharmaceutical Ingredients;Natural Plant Extract
• Mol File: 479-41-4.mol

Chemical Properties

• Melting Point: 350°C(lit.)
• Boiling Point: 496.6 °C at 760 mmHg
• Flash Point: 207 °C
• Appearance: /
• Density: 1.417 g/cm³
• Vapor Pressure: 5.34E-10mmHg at 25°C
• Refractive Index: 1.709
• Storage Temp.: -20°C
• Solubility: DMSO (Slightly), Methanol (Very Slightly, Heated)
• PKA: 9.13±0.20(Predicted)
• CAS DataBase Reference: Indirubin(CAS DataBase Reference)
• NIST Chemistry Reference: Indirubin(479-41-4)
• EPA Substance Registry System: Indirubin(479-41-4)

Safety Data

• RTECS: DU2995000
• Hazardous Substances Data: 479-41-4(Hazardous Substances Data)

Usage

References

[1] Tina Bla?evi?, Elke H. Heiss, Atanas G. Atanasov, Johannes M. Breuss, Verena M. Dirsch and Pavel Uhrin, Indirubin and Indirubin Derivatives for Counteracting Proliferative Diseases, Evidence-Based Complementary and Alternative Medicine, 2015, vol. 2015, Article ID 654098 [2] Ralph Hoessel, Sophie Leclerc, Jane A. Endicott, Martin E. M. Nobel, Alison Lawrie, Paul Tunnah, Maryse Leost, Eve Damiens, Dominique Marie, Doris Marko, Ellen Niederberger, Weici Tang, Gerhard Eisenbrand and Laurent Meijer, Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases, Nature Cell Biology, 1999, vol. 1, 60-67

Physical properties

Appearance: dark red acicular crystal with sublimate, odorless, and tasteless. Solubility: slightly soluble in dimethyl sulfoxide (DMSO) or tetrahydrofuran, very slightly soluble in chloroform or acetone, and insoluble in ethanol, ethyl ether, or water. Melting point: 348–353 °C. The stability of indirubin is poor that it needs to be stored away from light and thermal environment.

History

The report in 1951 showed that indirubin can inhibit eosinophils in the blood of guinea pigs. But this report did not attract attention. Indirubin is the effective component of the traditional Chinese medicine Angelica aloe pill. Since 1966, the scientists in the Institute of Hematonosis, Chinese Academy of Medical Sciences Research, started the research of therapying chronic myelocytic leukemia with the TCM rules using Angelica aloe pills, which had certain effect. Angelica aloe pill consisted of 11 herbs, such as Angelica, Aloe, Rhizoma Coptidis, and natural indigo. It was identified that natural indigo was the effective component of Angelica aloe pill. However, the active ingredient of natural indigo was indirubin.Indirubin is a novel antileukemia drug, which was found by the medical scientists in China in the middle of the 1970s. It has the effects of antibacterial, antiinflammatory, antitumor, and enhancing immune functions. The compound has been applied to the clinical treatment of chronic myeloid leukemia. Indirubin has the characteristics of reliable clinical curative effect, small side effects, and no obvious inhibitory effect on the bone marrow.

Uses

Different sources of media describe the Uses of 479-41-4 differently. You can refer to the following data:
1. Indigopurpurin is a purple 3,2-bisindole derivative and was shown to exhibit inhibitory allergic contact dermatitis via regulating T helper (Th)-mediated immune system in DNCB-induced model.
2. An inhibitor of GSK-3β and cyclin-dependent kinases.
3. Indigopurpurin is a purple 3,2-bisindole derivative and was shown to exhibit inhibitory allergic contact dermatitis via regulating T helper (Th)-mediated immune system in DNCB-induced model. A possible glycogen synthase kinase-3 (GSK-3) inhibitor the active component of a traditional Congolese antiepilepsy treatment.

Indications

Indirubin is contained in the fourth volume of the book, “National standards for chemical drugs.” Indirubin tablets are used for the therapy of chronic myelocytic leukemia in clinical.

General Description

This substance is a primary reference substance with assigned absolute purity (considering chromatographic purity, water, residual solvents, inorganic impurities). The exact value can be found on the certificate. Produced by PhytoLab GmbH & Co. KG

Pharmacology

The effect of indirubin has anti-inflammatory, antibacterial, detoxification, enhancing immune function anticancer. Indirubin has moderate inhibitory effect for animal-transplanted tumor. 200? mg/kg indirubin subcutaneous or intraperitoneal injection, once daily for 6 consecutive days, had the inhibition effect to rat W256 tumor cancer sarcoma; the inhibition rates were 47–52% and 50–58%, respectively. The chemotherapy index of intraperitoneal injection was 2.23. However, the inhibition rate of 500?mg/kg indirubin by gavage was only 23–33%. Indirubin by perfusion can prolong the survival time of W526 rat. The inhibition rate of Lewis mice’s lung cancer was 43% for 500?mg/kg indirubin orally, once a day for 9–10?days. Indirubin has some inhibition effects on mice breast cancer, but no obvious effect for L1212, P388, and L1210 of lymphocytic leukemia in mice.The effect of indirubin on chronic myelogenous leukemia is very obvious, which is similar to first clinical choice of Maryland. Indirubin has the advantages of fast curative effect, no obvious inhibition effect of the bone, small bone marrow toxicity, and low side effects. Indirubin may have the effect of improving adrenocorticotropic hormone. In pathological conditions, such as inflammatory diarrhea, protein metabolism disorder, kidney disease, leukemia, and other tumors, urinary excretion of indirubin increased. Indirubin can inhibit synthesis of DNA and destroy the leukemia cells. It was found by electron microscopy that juvenile cells reduced, even disappear completely, with indirubin administration. Indirubin can significantly reduce the size of spleen, increase the concentration of hemoglobin to normal level, and reduce the swelling liver. In addition, indirubin can also enhance the phagocytic ability of animal mononuclear macrophages, which play a role in body immune reaction. So the anticancer effect of this product may be related to improving the body’s immunity.

Clinical Use

Indirubin is mainly used for chronic myeloid leukemia; its total effective rate was 87.3%. The effect of indirubin to decrease white blood cells is similar to Maryland. The effect of indirubin to reduce liver is better than that of Maryland. But the remission role of the blood and bone marrow is worse than Maryland, and no cross resistance with Maryland. Indirubin could be used for abnormal bone marrow hyperplasia and eosinophilia.

in vitro

indirubin exerted its inhibitory effects not only on interferon-γ production by human myelomonocytic hbl-38 cells but also on interferon-γ and interleukin-σ production by murine splenocytes with no influence on the proliferation of either cells [1].

in vivo

because of indirubin’s inhibitory activity on interferon-γ production, the authors further investigated the effects of indirubin on 2,4,6-trinitro-l-chlorobenzene-induced delayed-type hypersensitivity. when injected intraperitoneally, indirubin significantly inhibited the ear swelling of tncb-elicited mice. moreover,the amount of interferon-γ in the culture supernatants of elicited mouse lymphocytes was inhibited by indirubin treatment [1].

InChI:InChI=1/C16H10N2O2/c19-15-10-6-2-4-8-12(10)17-14(15)13-9-5-1-3-7-11(9)18-16(13)20/h1-8,17H,(H,18,20)

Upstream product

• 59-48-3 2-oxoindole 
• 612-54-4 2-chloro-3H-indol-3-one 
• 71-43-2 benzene 
• 607-28-3 (E)-1H-indole-2,3-dione 3-oxime 
• 6245-93-8 3-hydroxy-1H-indole-2-carboxylic acid 
• 5588-87-4 1H-benzo[e]indole-1,2(3H)-dione 
• 64-19-7 acetic acid 
• 608-08-2 3-indoxyl acetate 
• 6411-55-8 2-phenylimino-indolin-3-one 
• 91-56-5 indole-2,3-dione 
• 480-93-3 indoxyl 
• 120-72-9 indole 
• 7664-93-9 sulfuric acid 
• 61-71-2 dioxindol 

Downstream Products

• 82349-14-2 (Z)-1'-benzoyl-1H,1'H-[2,3']biindolylidene-3,2'-dione 
• 160807-49-8 indirubin-3'-monoxime 
• 667463-82-3 indirubin-3'-monoxime 
• 91-56-5 indole-2,3-dione 
• 120-72-9 indole 
• 482-89-3 1H,1H'-2,2'-Biindolylidene-3,3'-dione 
• 160807-49-8 indirubin-3'-monoxime 
• 160807-49-8 indirubin-3'-oxime 
• 160807-49-8 indirubin-3'-oxime 
• 80789-74-8 5-isatinsulfonic acid sodium salt 
• 82355-81-5 N1-ethylindirubin 
• 1023287-68-4 allyl 2-(N-allylamino)benzoate 
• 830-74-0 1-allyl-1H-indole-2,3-dione 

Relevant articles and documents

A theoretical and spectroscopic (NMR and IR) study of indirubin in solution and in the solid state

The infrared spectrum of indirubin in the solid state and the 1H, 13C and 15N NMR spectra in DMSO-d6 solution as well as the 13C and 15N CPMAS spectra have been recorded. Different types of calculations (B3LYP, GIAO, and GIPAW) have been carried out. Experimental and calculated values were compared yielding commensurate results. E/Z isomerism was explored, as was oxo/hydroxy tautomerism.

Ecological Roles of Tryptanthrin, Indirubin and N-Formylanthranilic Acid in Isatis indigotica: Phytoalexins or Phytoanticipins?

Leaves of the plant species Isatis indigotica Fortune ex Lindl. (Chinese woad) produce the metabolites tryptanthrin, indirubin and N-formylanthranilic acid upon spraying with an aqueous solution of copper chloride but not after spraying with water. The antifungal activities of these metabolites against the phytopathogens Alternaria brassicicola, Leptosphaeria maculans and Sclerotinia sclerotiorum established that tryptanthrin is a much stronger growth inhibitor of L. maculans than the phytoalexin camalexin. The biosynthetic precursors of tryptanthrin and N-formylanthranilic acid are proposed based on the deuterium incorporations of isotopically labeled compounds. The overall results suggest that tryptanthrin is a phytoalexin and indirubin and N-formylanthranilic acid are phytoanticipins in the plant species I. indigotica and that chemical diversity and biodiversity are intimately connected.

A novel indigoid anti-tuberculosis agent

The structure of a novel indigoid component was characterized by X-ray crystallography. This compound exhibited excellent anti-tuberculosis activity against Mycobacterium tuberculosis H37Rv in whole cell culture showing a submicromolar minimum inhibitory concentration (MIC). A synthesis of this molecule was designed and carried out to produce sufficient material for further testing. The in vitro profile, structure, and first synthesis of this indigoid component is reported.

One step synthesis of indirubins by reductive coupling of isatins with KBH4

One step synthesis of the natural product indirubin by reductive coupling of isatin with KBH4 is described and a possible mechanism for the reaction is proposed. Eleven indirubin derivatives were obtained easily from the corresponding substituted isatin.

Design, synthesis and biological evaluation of bisindole derivatives as anticancer agents against Tousled-like kinases

This study presents the design, synthesis, and characterization of bisindole molecules as anti-cancer agents against Tousled-like kinases (TLKs). We show that compound 2 composed of an indirubin-3′-oxime group linked with a (N-methylpiperidin-2-yl)ethyl moiety possessed inhibitory activity toward both TLK1 and TLK2 in vitro and diminished the phosphorylation level of the downstream substrate anti-silencing function 1 (ASF1) in replicating cells. The treatment of compound 2 impaired DNA replication, slowed S-phase progression, and triggered DNA damage response in replicating cells. Structure optimization further discovered six derivatives exhibiting potent TLK inhibitory activity and revealed the importance of the tertiary amine-containing moiety of the side chain. Moreover, the derivatives 6, 17, 19, and 20 strongly suppressed the growth of triple-negative breast cancer MDA-MB-231 cells, non-small cell lung cancer A549 cells, and colorectal cancer HCT-116 cells, while normal lung fibroblast MRC5 and IMR90 cells showed a lower response to these compounds. Taken together, this study identifies tertiary amine-linked indirubin-3′-oximes as potent anticancer agents that inhibit TLK activity.

A tunable synthesis of indigoids: Targeting indirubin through temperature

The spontaneous conversion of 3-indoxyl to indigo is a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids. This journal is

Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer

To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound 8b with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC50 = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound 8b can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound 8b showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound 8b as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.

All-Red-Light Photoswitching of Indirubin Controlled by Supramolecular Interactions

Red-light responsiveness of photoswitches is a highly desired property for many important application areas such as biology or material sciences. The main approach to elicit this property uses strategic substitution of long-known photoswitch motives such as azobenzenes or diarylethenes. Only very few photoswitches possess inherent red-light absorption of their core chromophore structures. Here, we present a strategy to convert the long-known purple indirubin dye into a prolific red-light-responsive photoswitch. In a supramolecular approach, its photochromism can be changed from a negative to a positive one, while at the same time, significantly higher yields of the metastable E-isomer are obtained upon irradiation. E- to Z-photoisomerization can then also be induced by red light of longer wavelengths. Indirubin therefore represents a unique example of reversible photoswitching using entirely red light for both switching directions.

Composition for Inhibiting or Treating for Acute Myeloid Leukemia or Metastatic Breast Cancer

The present invention relates to a pharmaceutical composition for preventing or treating acute myeloid leukemia or metastatic breast cancer comprising an indirubin derivative as an active ingredient. Use of the composition of the invention effectively inhibits the activity of FLT3 kinase. A composition for preventing or treating acute myeloid leukemia or metastatic breast cancer is provided.

Exploring an anomaly: The synthesis of 7,7′-diazaindirubin through a 7-azaindoxyl intermediate

Two independent methods generating 7-azaindoxyl as an intermediate verify that 7,7′-diazaindirubin is formed exclusively over 7,7′-diazaindigo. This contrasts with long-standing knowledge related to the reactivity of indoxyl, which proceeds via a radical-initiated homodimerization process, leading to indigo. A series of experiments confirms 7-azaindoxyl as an intermediate with results suggesting a condensation pathway followed by oxidation.