160807-49-8

Basic information

• Product Name: INDIRUBIN-3'-MONOXIME
• Synonyms: 3-[1,3-DIHYDRO-3-(HYDROXYIMINO)-2H-INDOL-2-YLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE;INDIRUBIN-3'-MONOXIME;INDIRUBIN-3'-OXIME;Indirubine-3'-oxime;INDIRUBIN-3’-MONOOXIME;Indirubin-3'Indirubin-3′Indirubin-3
• CAS NO: 160807-49-8
• Molecular Formula: C16H11N3O2
• Molecular Weight: 277.28
• Product Categories: Aromatic Hydrazides, Hydrazines, Hydrazones and Oximes;Inhibitors;Protein Kinase;Intracellular Signaling
• Mol File: 160807-49-8.mol
• Article Data: 23

Chemical Properties

• Melting Point: 247-249°C
• Boiling Point: 532.2±50.0 °C(Predicted)
• Appearance: /solid
• Density: 1.50
• Storage Temp.: Store at RT
• Solubility: DMSO: >10 mg/mL
• PKA: 8.66±0.20(Predicted)
• Water Solubility: DMSO: >10 mg/mL
• Stability: Light Sensitive
• CAS DataBase Reference: INDIRUBIN-3'-MONOXIME(CAS DataBase Reference)
• NIST Chemistry Reference: INDIRUBIN-3'-MONOXIME(160807-49-8)
• EPA Substance Registry System: INDIRUBIN-3'-MONOXIME(160807-49-8)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 160807-49-8(Hazardous Substances Data)

Usage

Description

Indirubin-3’-oxime is a potent inhibitor of glycogen synthase kinase 3β (GSK3β; IC50 = 22 nM). As GSK3β phosphorylates tau protein, indirubin-3’-oxime prevents tau phosphorylation both in vitro and in vivo at Alzheimer’s disease-relevant sites. It also inhibits cyclin-dependent kinases (CDKs) at higher concentrations, including Cdk1/cyclin B (IC50 = 180 nM), Cdk2/cyclin A (IC50 ~500 nM), Cdk2/cyclin E (IC50 = 250nM), Cdk4/cyclin D1 (IC50 = 3.3 μM) and Cdk5/p35 (IC50 = 100 nM). Indirubin-3’-oxime reversibly inhibits the proliferation of many cells types, arresting cycling in the G2/M phase.

Chemical Properties

Dark Red Solid

Uses

Different sources of media describe the Uses of 160807-49-8 differently. You can refer to the following data:
1. A potent inhibitor of GSK-3? (IC50=22nM). Also inhibits CDK1 (IC50=180nM) and CDK (IC50=100nM). It reversibly arrests asynchronous HBL-100 cells at G2. It induces apoptosis in the mammary carcinoma cell line MCF-7 (10üM).
2. Indirubin-3′-oxime has been used in the inhibition of glycogen synthase kinase 3 in human monocytic cell line, THP-1.

Biological Activity

Protein kinase inhibitor: inhibits cyclin-dependent kinases (IC 50 = 0.18-3.33 μ M) and GSK-3 β (IC 50 = 0.19 μ M). Inhibits CDK5- and GSK-3 β -mediated tau phosphorylation, a process over-active in Alzheimer disease states. Also inhibits AMPK, LCK and SGK. Induces cell cycle arrest and inhibits cell proliferation.

Biochem/physiol Actions

Indirubin-3′-oxime is a cyclin-dependent kinase inhibitor which functions by competing with ATP for binding to the catalytic subunit; exhibits antiproliferative activity leading to G2/M arrest in many cell lines and G1/S arrest in Jurkat cells.

References

1) Leclerc?et al. (2001),?Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors?; J. Biol. Chem.,?276?251 2) Damiens?et al. (2001),?Anti-mitotic properties of indirubin-3′-monoximine, a CDK/GSK-3 inhibitor: induction of endoreplication following prophase arrest; Oncogene,?20?3786 3) Kim?et al. (2011),?Indirubin-3′-monoxime, a derivative of a chinese antileukemia medicine, inhibits angiogenesis; J. Cell. Biochem.,?112?1384 4) Ding?et al. (2010),?Indirubin-3′-monoxime rescues spatial memory deficits and attenuates beta-amyloid-associated neuropathology in a mouse model of Alzheimer’s disease; Neurobiol. Dis.,?39?156

InChI:InChI=1/C16H11N3O2/c20-16-13(9-5-1-3-7-11(9)18-16)15-14(19-21)10-6-2-4-8-12(10)17-15/h1-8,17,21H,(H,18,20)/b15-13-,19-14+

Upstream product

• 91-56-5 indole-2,3-dione 
• 608-08-2 3-indoxyl acetate 
• 479-41-4 indirubin 
• 479-41-4 indirubin 
• 6146-52-7 5-nitroindole 
• 479-41-4 indirubin 
• 16800-67-2 N,O-diacetylindoxyl 
• 612-42-0 phenylglycine-o-carboxylic acid 
• 88-65-3 2-bromobenzoic-acid 
• 1415677-96-1 (2R)-2-(acetyloxy)-4-({[(2Z,3E)-2-(1,2-dihydro-2-oxo-3H-indol-3-ylidene)-1,2-dihydro-3H-indol-3-ylidene]amino}oxy)-N,N,N-trimethyl-4-oxobutan-1-aminium chloride 

Downstream Products

• 854171-35-0 indirubin-3′-(3,4-dihydroxybutyl)oxime ether 

Relevant articles and documents

Studies on the acetylation and NMR reassignment of indirubin derivatives

The analysis of 1D- and 2D-NMR spectroscopic data confirmed that the amino N-1' protons of indirubin and indirubin-3'-oxime resonate at a higher frequency than N-1 protons. The amino N-1' protons in both indirubin and indirubin-3'-oxime are not favourable for acetylated reaction due to their intramolecular hydrogen bonding with the amide carbonyl group. The new N-1-acetylindirubin-3'-acetoxime has been synthesised using acetic anhydride. The reassignment of the NMR data of indirubin, indirubin-3'-oxime and N-1-acetylindirubin was confirmed with the aid of DEPT, HSQC, HMBC and NOESY methods.

The synthesis, antileukemic activity, and crystal structures of indirubin derivatives

In order to search for a new kind of antileukemic drug, we synthesized four indirubin derivatives, including indirubin monooxime (IM), indirubin monooxime O-methyl ether (IMME), N1-methylindirubin monooxime O-methyl ether (MIMME), and indirubin monooxime O-ethyl ether (IMEE). Their antileukemic activities in vivo and in vitro were tested; some of these compounds showed good activities. Their molecular and crystal structures were determined by an X-ray diffraction method. The results revealed that all four indirubin derivatives are planar, and have a tendency to form a big π-system. The molecular structures also showed that oximation of indirubin resulted in only a slight change in the antileukemic activity. On the other hand, the amido moiety in the compounds may play an important role in the activity of the indirubin monooxime derivatives. This conclusion was supported by the calculation results of the electrostatic-potential (esp) derived charge distribution of the indirubin derivatives, which were obtained using an ab initio molecular orbital of the basis set (3-21G), taking the electronic correlation into account at the MP2 level.

Discovery of orally active indirubin-3′-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia

FMS-like receptor tyrosine kinase-3 (FLT3) is expressed on acute leukemia cells and is implicated in the survival, proliferation and differentiation of hematopoietic cells in most acute myeloid leukemia (AML) patients. Despite recent achievements in the development of FLT3-targeted small-molecule drugs, there are still unmet medical needs related to kinase selectivity and the progression of some mutant forms of FLT3. Herein, we describe the discovery of novel orally available type 1 FLT3 inhibitors from structure-activity relationship (SAR) studies for the optimization of indirubin derivatives with biological and pharmacokinetic profiles as potential therapeutic agents for AML. The SAR exploration provided important structural insights into the key substituents for potent inhibitory activities of FLT3 and in MV4-11 cells. The profile of the most optimized inhibitor (36) showed IC50 values of 0.87 and 0.32 nM against FLT3 and FLT3/D835Y, respectively, along with potent inhibition against MV4-11 and FLT3/D835Y expressed MOLM14 cells with a GI50 value of 1.0 and 1.87 nM, respectively. With the high oral bioavailability of 42.6%, compound 36 displayed significant in vivo antitumor activity by oral administration of 20 mg/kg once daily dosing schedule for 21 days in a mouse xenograft model. The molecular docking study of 36 in the homology model of the DFG-in conformation of FLT3 resulted in a reasonable binding mode in type 1 kinases similar to the reported type 1 FLT3 inhibitors Crenolanib and Gilteritinib.

Synthesis of methoxy- and bromo-substituted indirubins and their activities on apoptosis induction in human neuroblastoma cells

This paper reports the synthesis of methoxy- and bromo-indirubins, and their antiproliferative activities in human neuroblastoma. Among 20 compounds, 5'-methoxyindirubin induced cell death in human neuroblastoma cells (IMR-32, SK-N-SH and NB-39) without inhibiting normal cells (NHDF and HUVEC). Typical morphologic features of apoptosis were observed in 5′-methoxyindirubin- treated cells by Hoechst 33342 staining. Additional studies by flow cytometry support apoptosis induction. These data suggest that 5′-methoxyindirubin might be an effective drug for treatment of neuroblastoma.

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-derived degradation agent as well as preparation and application thereof

The invention belongs to the technical field of medicinal chemistry, and particularly relates to an indirubin-derived degradation agent and preparation and application thereof. The indirubin-derived degradation agent prepared through the method can degrade HDAC6 in a targeted mode, so that application in preparation of HDAC6 degradation agents or anti-inflammatory drugs is achieved. The indirubin-derived degradation agent has low toxicity and excellent anti-inflammatory activity, and the quality and the safety of products are ensured.