667463-82-3

Upstream product

• 91-56-5 indole-2,3-dione 
• 608-08-2 3-indoxyl acetate 
• 16800-67-2 N,O-diacetylindoxyl 
• 612-42-0 phenylglycine-o-carboxylic acid 
• 88-65-3 2-bromobenzoic-acid 
• 479-41-4 indirubin 
• 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 

Relevant academic research and scientific papers

Water-soluble cationic derivatives of indirubin, the active anticancer component from indigo naturalis

To overcome the problem of poor aqueous solubility and bioavailability of indirubin-3-oximes, the compounds were modified by attaching a quaternary ammonium group at the oxime moiety. Exploring the prodrug concept, an oxime ester with acetyl-l-carnitine was prepared, and the rate of its hydrolysis was investigated to assess its suitability for clinical administration. In addition, the cytotoxic potency of new stable oxime ethers with a choline moiety and their influence on the cell cycle were tested in human cancer cell lines.

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.

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.

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.

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 new indirubin derivatives and their in vitro anticancer activity

The opening of epoxy rings from (2′Z)-N-1-(oxiran-2-ylmethyl)indirubin (2) and (2′Z-3′E)-indirubin-3?-[O-oxiran-2-ylmethyl)oxime] (6) with thiols gave 17 new derivatives of indirubin in good yields. Their structures were elucidated by 1D-, 2D-NMR and HRMS

Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases

Pharmacological inhibitors of glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases have a promising potential for applications against several neurodegenerative diseases such as Alzheimer's disease. Indirubins, a family of bis-indoles isolated from various natural sources, are potent inhibitors of several kinases, including GSK-3. Using the cocrystal structures of various indirubins with GSK-3β, CDK2 and CDK5/p25, we have modeled the binding of indirubins within the ATP-binding pocket of these kinases. This modeling approach provided some insight into the molecular basis of indirubins' action and selectivity and allowed us to forecast some improvements of this family of bis-indoles as kinase inhibitors. Predicted molecules, including 6-substituted and 5,6-disubstituted indirubins, were synthesized and evaluated as CDK and GSK-3 inhibitors. Control, kinase-inactive indirubins were obtained by introduction of a methyl substitution on N1.

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.