- A theoretical and spectroscopic (NMR and IR) study of indirubin in solution and in the solid state
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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.
- Alkorta, Ibon,Elguero, José,Dardonville, Christophe,Reviriego, Felipe,Santa María, Dolores,Claramunt, Rosa M.,Marín-Luna, Marta
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- Ecological Roles of Tryptanthrin, Indirubin and N-Formylanthranilic Acid in Isatis indigotica: Phytoalexins or Phytoanticipins?
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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.
- Pedras, M. Soledade C.,Abdoli, Abbas,To, Q. Huy,Thapa, Chintamani
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Read Online
- A novel indigoid anti-tuberculosis agent
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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.
- Klein, Larry L.,Petukhova, Valentina,Wan, Baojie,Wang, Yuehong,Santasiero, Bernard D.,Lankin, David C.,Pauli, Guido F.,Franzblau, Scott G.
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Read Online
- One step synthesis of indirubins by reductive coupling of isatins with KBH4
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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.
- Wang, Cuiling,Yan, Jiaxu,Du, Mo,Burlison, Joseph A.,Li, Chi,Sun, Yanni,Zhao, Danqing,Liu, Jianli
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- Design, synthesis and biological evaluation of bisindole derivatives as anticancer agents against Tousled-like kinases
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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.
- Lee, Sung-Bau,Chang, Ting-Yu,Lee, Nian-Zhe,Yu, Zih-Yao,Liu, Chi-Yuan,Lee, Hsueh-Yun
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- A tunable synthesis of indigoids: Targeting indirubin through temperature
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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
- Cheek, Joshua T.,Horner, John S.,Kaller, Kaylie S.,Kinsey, Ally L.,Shriver, James A.,Sterrenberg, Summer R.,Van Vors, Madison K.,Wang, Katelyn R.
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p. 5407 - 5414
(2022/03/01)
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- All-Red-Light Photoswitching of Indirubin Controlled by Supramolecular Interactions
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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.
- Dube, Henry,Hoffmann, Nadine,K?ttner, Laura,Mayer, Peter,Thumser, Stefan
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supporting information
p. 18251 - 18260
(2021/11/12)
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- Composition for Inhibiting or Treating for Acute Myeloid Leukemia or Metastatic Breast Cancer
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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.
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Paragraph 0064; 0074-0078
(2021/05/11)
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- Indirubin Derivatives as Dual Inhibitors Targeting Cyclin-Dependent Kinase and Histone Deacetylase for Treating Cancer
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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.
- An, Jianxiong,Cao, Zhuoxian,Gu, Zhicheng,He, Bin,Li, Yan,Li, Yongjun,Lin, Hening,Lin, Shuxian,Liu, Ting,Wang, Jie,Wang, Pan,Yang, Fenfen,Zhao, Yonglong
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p. 15280 - 15296
(2021/10/25)
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- Syntheses of indirubins by aldol condensation of isatins with indoxyl anion generated in situ by lipase-catalyzed deacetylation of indoxyl acetate
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The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous
- Hanaya, Kengo,Higashibayashi, Shuhei,Sugai, Takeshi
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p. 129 - 136
(2020/01/28)
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- Discovery of orally active indirubin-3′-oxime derivatives as potent type 1 FLT3 inhibitors for acute myeloid leukemia
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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.
- Choi, Jungil,Han, Sun-Young,Heo, Jeong Doo,Jeong, Pyeonghwa,Kim, Jiheon,Kim, Na Yoon,Kim, Yong-Chul,Kim, Yoon-Gyoon,Lee, Hyo Jeong,Lee, Je-Heon,Lee, Jungeun,Lee, So-Deok,Moon, Yeongyu,Park, Hyun Woo,Park, Jiyeon,Shin, Ji Eun
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- Exploring an anomaly: The synthesis of 7,7′-diazaindirubin through a 7-azaindoxyl intermediate
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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.
- DeYoung, James R.,Lipsius, Richard J.,Patterson, Andrew C.,Shriver, James A.,Wang, Katelyn R.
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p. 36849 - 36852
(2020/10/26)
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- Indirubin derivative used in combination with polypeptide as well as preparation method and application of indirubin derivative
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The invention relates to an indirubin derivative used in combination with polypeptide as well as a preparation method and application of the indirubin derivative, and belongs to the technical field ofmedicinal chemistry. The structure of the compound is shown as a general formula I. The indirubin derivative provided by the invention has an obvious inhibition effect on leukemia cells K562, and theinhibition strength on tumor cells is remarkably improved after the indirubin derivative is combined with polypeptide drug blue peptide. The compound as shown in the general formula I can be appliedto preparation of drugs for treating leukemia or lead compounds developed as drugs for treating leukemia, or used for preparing drugs for treating leukemia and combined with polypeptide drugs.
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- Lenalidomide derivative capable of inhibiting IDO1 activity as well as preparation method and application of lenalidomide derivative
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The invention relates to a lenalidomide derivative capable of inhibiting IDO1 activity as well as a preparation method and application of the lenalidomide derivative, and belongs to the technical field of medicinal chemistry. The structure of the compound is shown as a general formula I. The activity inhibition effect of the lenalidomide derivative provided by the invention on IDO1 is obviously superior to that of indirubin, lenalidomide and pomalidomide. The compound shown in the general formula I can be applied to preparation of drugs for inhibiting the activity of IDO1.
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- Elucidating Cysteine-Assisted Synthesis of Indirubin by a Flavin-Containing Monooxygenase
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Indirubin is a biologically active compound found in Danggui Longhui Wan, which is a traditional Chinese medicine for chronic myelocytic leukemia. In the biosynthesis of indirubin, the formation of indigo, which is a stereoisomer of indirubin, is a major side reaction. Recent findings have suggested that cysteine supplementation shifts product selectivity from indigo to indirubin. Here, we disclose how cysteine is involved in enhancing the product selectivity in the synthesis of indirubin using a flavin-containing monooxygenase from Methylophaga aminisulfidivorans (MaFMO). First, cysteine reacts with indoxyl to synthesize 2-cysteinylindoleninone, inhibiting the dimerization of indoxyl. Second, the reducing power of cysteine allows MaFMO to additionally hydroxylate indoxyl toward isatin, overcoming the problem in biased distribution of two different precursors. Third, cysteine activates isatin to react with 2-cysteinylindoleninone to form indirubin. Based on this revealed mechanism, indirubin derivatives with different indole ring components were synthesized.
- Kim, Joonwon,Lee, Jeongchan,Lee, Pyung-Gang,Kim, Eun-Jung,Kroutil, Wolfgang,Kim, Byung-Gee
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p. 9539 - 9544
(2019/10/14)
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- A biomimetic, one-step transformation of simple indolic compounds to malassezia-related alkaloids with high ahr potency and efficacy
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Malassezia furfur isolates from diseased skin preferentially biosynthesize compounds which are among the most active known aryl-hydrocarbon receptor (AhR) inducers, such as indirubin, tryptanthrin, indolo[3,2-b]carbazole, and 6-formylindolo[3,2-b]carbazole. In our effort to study their production from Malassezia spp., we investigated the role of indole-3-carbaldehyde (I3A), the most abundant metabolite of Malassezia when grown on tryptophan agar, as a possible starting material for the biosynthesis of the alkaloids. Treatment of I3A with H2O2 and use of catalysts like diphenyldiselenide resulted in the simultaneous one-step transformation of I3A to indirubin and tryptanthrin in good yields. The same reaction was first applied on simple indole and then on substituted indoles and indole-3-carbaldehydes, leading to a series of mono- A nd bisubstituted indirubins and tryptanthrins bearing halogens, alkyl, or carbomethoxy groups. Afterward, they were evaluated for their AhR agonist activity in recombinant human and mouse hepatoma cell lines containing a stably transfected AhR-response luciferase reporter gene. Among them, 3,9-dibromotryptanthrin was found to be equipotent to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as an AhR agonist, and 3-bromotryptanthrin was 10-times more potent than TCDD in the human HG2L7.5c1 cell line. In contrast, 3,9-dibromotryptanthrin and 3-bromotryptanthrin were 4000 and >10,000 times less potent than TCDD in the mouse H1L7.5c3 cell line, respectively, demonstrating that they are species-specific AhR agonists. Involvement of the AhR in the action of 3-bromotryptanthrin was confirmed by the ability of the AhR antagonists CH223191 and SR1 to inhibit 3-bromotryptanthrin-dependent reporter gene induction in human HG2L7.5c1 cells. In conclusion, I3A can be the starting material used by Malassezia for the production of both indirubin and tryptanthrin through an oxidation mechanism, and modification of these compounds can produce some highly potent, efficacious and species-selective AhR agonists.
- Mexia, Nikitia,Koutrakis, Stamatis,He, Guochun,Skaltsounis, Alexios-Leandros,Denison, Michael S.,Magiatis, Prokopios
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p. 2238 - 2249
(2019/11/19)
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- Pharmacological evaluation of novel PKR inhibitor indirubin-3-hydrazone in-vitro in cardiac myocytes and in-vivo in wistar rats
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Aims: Double stranded protein kinase R cellular response is associated with various stress signals such as nutrients, endoplasmic stress, cytokines and mechanical stress. Increased PKR activity has been observed under diabetic and cardiovascular disease conditions. Most of the currently available PKR inhibitors are non-specific and have other effects as well. Thus, the aim of the present study was to examine the effect of novel PKR inhibitor indirubin-3-hydrazone (IHZ) in cultured rat H9C2 cardiomyocytes and wistar rats. Materials and methods: PKR expression was determined by Q-PCR, immunofluorescence and immunoblotting. The expression of different gene markers for apoptosis was measured by RT-PCR. Apoptosis and oxidative stress were determined by flow cytometry. KEY FINDINGS: High glucose (HG) treated H9C2 cardiomyocytes and high fructose (HF) treated wistar rats developed a significant increase in PKR expression. A significant increase in apoptosis and generation of reactive oxygen species was also observed in HG treated H9C2 cells and HF treated rats. Reduced vacuole formation and prominent nuclei were also observed in high glucose treated cells. Cardiac hypertrophy and increased fibrosis were observed in HF treated rats. All these effects of HG and HF were attenuated by novel PKR inhibitor, indirubin-3-hydrazone. Significance: Our results indicate IHZ as an effective inhibitor of PKR in vitro and in-vivo, thus it may prove very useful in blocking the multiple harmful effects of PKR.
- Udumula, Mary Priyanka,Bhat, Audesh,Mangali, Sureshbabu,Kalra, Jaspreet,Dhar, Indu,Sriram, Dharamrajan,Dhar, Arti
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- Indirubin derivative or pharmacologically acceptable salt thereof for antitumor drug and preparation method
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The invention provides an indirubin derivative shown as the formula (I) in the specification or a pharmacologically acceptable salt thereof, a preparation method thereof, and application thereof in preventing or treating related diseases of abnormality of cell proliferation, particularly to drugs for preventing or treating tumors. The formula (I) is shown in the description.
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Paragraph 0017
(2017/08/31)
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- Indirubin derivatives protect against endoplasmic reticulum stress-induced cytotoxicity and down-regulate CHOP levels in HT22 cells
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Indirubin and its derivatives have been reported to exhibit anti-cancer and anti-inflammatory activities. Recently, some of its derived analogs have been shown to have neuroprotective potential. Endoplasmic reticulum (ER) stress has been demonstrated to contribute to the pathogenesis of various neurodegenerative diseases, whereas the effects of indirubin derivatives on ER stress-induced cell death have not been addressed. In the present study, a series of 44 derivatives of indirubin was prepared to search for a novel class of neuroprotective agents against ER stress-induced neuronal death. The MTT reduction assay indicated that tunicamycin (TM), an inducer of ER stress, significantly decreased the viability of hippocampal neuronal HT22 cells. Among the compounds tested, eight showed significant inhibitory activity against TM-induced cell death. Western blot analysis showed that application of these analogs to the cells simultaneously with TM reduced the TM-induced expression of CHOP, an established mediator of ER stress. Our results suggest that the preventive effect of these indirubin derivatives against ER stress-induced neuronal death may be due, at least in part, to attenuation of the CHOP-dependent signaling system.
- Kosuge, Yasuhiro,Saito, Hiroaki,Haraguchi, Tatsuki,Ichimaru, Yoshimi,Ohashi, Sachiyo,Miyagishi, Hiroko,Kobayashi, Shunsuke,Ishige, Kumiko,Miyairi, Shinichi,Ito, Yoshihisa
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p. 5122 - 5125
(2017/11/14)
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- Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule
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Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5-and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new indirubin 3′-and 5′-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor.
- Cheng, Xinlai,Merz, Karl-Heinz,Vatter, Sandra,Zeller, Jochen,Muehlbeyer, Stephan,Thommet, Andrea,Christ, Jochen,W?lfl, Stefan,Eisenbrand, Gerhard
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p. 4949 - 4962
(2017/06/28)
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- A biomimetic synthesis indirubin and derivatives thereof
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The invention provides a biomimetic synthesis method of indirubin. The biomimetic synthesis method of the indirubin comprises the following steps: adding an organic solvent and a reducing agent to isatin, reacting at the temperature of -10.0 to 150.0 DEG C for 0.5 to 72.0 hours, carrying out agitation backflow or solvent-free grinding, and then extracting so as to obtain the indirubin, wherein the mole ratio of the reducing agent to the isatin is (50 to 1)-(0.001 to 1), and the ratio of the isatin to the organic solvent (the mole to the volume) is 1 to (3-6); the synthesis method of indirubin derivatives is the same as the indirubin synthesis method. The biomimetic synthesis method is simple and direct in synthetic routes, mild in reaction conditions, high in yield and simple to operate, and the raw materials are low in cost and easy to obtain.
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Paragraph 0035; 0036
(2017/03/22)
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- Isatin derivatives with activity against apoptosis-resistant cancer cells
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In a search of small molecules active against apoptosis-resistant cancer cells, a series of isatin-based heterocyclic compounds were synthesized and found to inhibit proliferation of cancer cell lines resistant to apoptosis. The synthesis of these compounds involved a condensation of commercially available, active methylene heterocycles with isatin proceeding in moderate to excellent yields. The heterocyclic scaffolds prepared in the current investigation appear to be a useful starting point for the development of agents to fight cancers with apoptosis resistance, and thus, associated with dismal prognoses.
- Evdokimov, Nikolai M.,Magedov, Igor V.,McBrayer, Dominic,Kornienko, Alexander
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p. 1558 - 1560
(2016/07/27)
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- The behaviour of Bis(diphenylphosphino)alkanes towards different active centres
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Benzophenones (diarylmethanones) are important starting materials in the synthesis and preparation of organic compounds such as heat-resistant resins, various drugs, and natural products.1-7 1,1′-(Azodicarbonyl)dipiperidine has different pharmacological and biological activities.8-13 The versatility of isatin (1H-indole-2,3-dione) in synthetic organic chemistry is shown in its biological and pharmacological properties and its extensive use in organic synthesis.14 Moreover, quinoxaline 1,4-di-N-oxide is a building block that has a broad range of biological applications.15 Bis(diphenylphosphino)alkanes have been reported as anticancer agents.16-20The useful applications of these starting materials, coupled with our interest in organophosphorus chemistry,21-25 encouraged us to synthesise new organophosphorus compounds and to identify the preferred site of attack of these compounds. We sought to obtain the target compounds by reacting bis(diphenylphosphino) alkanes 1a-c with some different organic compounds; namely, benzophenone2, 1,1′-(azodicarbonyl)dipiperidine (ADDP, 3), isatin 4a and 4b, and quinoxaline 1,4-di-N-oxide 5 (Scheme 1).
- Ewies, Ewies F.,El-Sayed, Naglaa F.,Boulos, Leila S.
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p. 417 - 421
(2016/07/19)
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- Cyclization of cyanoethylated ketones as a route to 6-substituted indole derivatives
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δ-Cyanoketones are quickly cyclized with KOtBu to 3-aminocyclohex-2-enone derivatives, which in turn will give substituted indoles when treated with oxalyl chloride. Thus, 3-amino-6,6-dimethylcyclohex-2-enone gave 3-chloro-6,6-dimethyl-2,5,6,7-tetrahydroindole-2,5-dione, whose structure was corroborated by X-ray crystallography, whereas the corresponding molecule without the blocking gem-dimethyl groups, 3-aminocyclohex-2-enone, gave via hydrogen shifts 6-chloro-3-hydroxyoxindole.
- Bergman, Jan,Stensland, Birgitta
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- Biomimetic oxidation of indole by Mn(III)porphyrins
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The oxidation of indole under biomimetic conditions in the presence of Mn(III)porphyrins and using hydrogen peroxide as a green oxidant is described. The metalloporphyrins act as chemical models of the enzymes involved in the natural and biocatalytic oxidation of indole to afford indigo dye, but leading to simplified systems, with significantly lower cost requirements, as higher indole conversions and easier product isolation are obtained. The distribution of the products that include 2-oxoindole, isatin, 2,2′-bis(3′- indolyl)-3-oxoindole and the indigoid pigments, indigo and indirrubin, was found to be dependent on the reaction time, the amount of oxidant and the electronic characteristics of the metalloporphyrin catalyst. Upon 30 min of reaction time, 85% of indole conversion was achieved. The best conditions for pigment formation and isolation included the separation of the initially formed 3-indoxyl from the oxidizing reaction mixture, followed by heating to obtain the air oxidative dimerization.
- Linhares, Margarida,Rebelo, Susana L.H.,Sim?es, Mário M.Q.,Silva, Artur M.S.,Neves, M. Gra?a P.M.S.,Cavaleiro, José A.S.,Freire, Cristina
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p. 427 - 433
(2014/01/06)
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- INDIRUBIN DERIVATIVE HAVING HIGHLY SELECTIVE CYTOTOXICITY FOR MALIGNANT TUMORS
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An agent for treating malignant tumors based on a new mechanism is provided, which comprises an indirubin derivative represented by formula (1) or a salt thereof: wherein A represents an alkylene group having 1 to 4 carbon atoms, and R1 to R4 each independently represent a hydrogen atom, a halogen atom, a hydroxy group, or an alkoxy group.
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Paragraph 0034; 0035; 0036
(2014/06/11)
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- PRODUCTION OF RED BLOOD CELLS AND PLATELETS FROM STEM CELLS
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This disclosure provides methods of making a megakaryocyte-erythroid progenitor cell (MEP), comprising differentiating a stem cell into a MEP in culture in the presence of an aryl hydrocarbon receptor (AhR) agonist. In some embodiments the stem cell is a pluripotent stem cell. In some embodiments the MEP co-expresses CD41 and CD235. In some embodiments the number of MEPs produced in the culture increases exponentially. Methods of making a red blood cell (RBC) by culturing a MEP in the presence of an AhR agonist are also provided. Methods of making a megakaryocyte and/or a platelet, comprising culturing a MEP in the presence of an AhR modulator are also provided. In some embodiments the AhR modulator is an AhR antagonist. This disclosure also provides compositions comprising at least 1 million MEPs per ml and compositions in which at least 50% of the cells are MEPs.
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- Indigo dye production by enzymatic mimicking based on an iron(III)porphyrin
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A novel indigo synthesis is based on a simple and cost-effective model system of the enzymes involved in the natural and biocatalytic productions. The method considers the oxidation of indole by hydrogen peroxide, being catalyzed by an iron(III)porphyrin in ethanol, as solvent, and no other additives. The yields of indigo and of the other oxidized indolinoid derivatives were found to be dependent on the metalloporphyrin system used and on the control of the oxidation conditions. Significant reductions of the environmental impact relatively to the present industrial production and of the costs relatively to the biocatalytic methodologies were obtained. The enhanced indigo production in the presence of the iron(III)porphyrin-ethanol catalytic system relatively to the manganese(III)porphyrin-acetonitrile system can be rationalized by the formation of different active species in the two systems.
- Rebelo, Susana L.H.,Linhares, Margarida,Simoes, Mario M.Q.,Silva, Artur M.S.,Neves, M. Graca P.M.S.,Cavaleiro, Jose A.S.,Freire, Cristina
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- Formation of tryptanthrin compounds upon Oxone-induced dimerization of indole-3-carbaldehydes
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Tryptanthrin is a natural product with numerous important pharmacological properties. Tryptanthrin and its analogs are commonly prepared by condensation of isatoic anhydride and isatin. In this Letter we investigate the formation of tryptanthrin derivatives upon Oxone-induced oxidative dimerization of indole-3-carbaldehydes.
- Nelson, Amber C.,Kalinowski, Emily S.,Jacobson, Taylor L.,Grundt, Peter
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p. 6804 - 6806
(2013/11/19)
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- Improved synthesis of indirubin derivatives by sequential build-up of the indoxyl unit: First preparation of fluorescent indirubins
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Indirubin, present in extracts of Isatis tinctoria and some other plant species, has promising cytotoxicity against a variety of cell lines by inhibition of cyclin-dependent kinases. Chemical synthesis of its derivatives relies on the combination of isatins and 2,3-dihydro-1H-indol-3-one ('indoxyl') derivatives and usually yields indigo as well as other by-products. Inspection of the hydrolysis of the long-known condensation products of 2-thioxothiazolidin-4-one with isatins gave useful hints for an improved synthesis of indirubins: this reaction does not yield quinoline derivatives but 2-(2,3-dihydro-2-oxo-1H-indol-3-ylidene)-2-sulfanyl acetic acids. By substitution of the sulfanyl group in this oxindoles with anilines and straightforward cyclization under Nazarov conditions, a broad variety of indirubins substituted in the indoxyl ring system are thus available, usually in very good purity and yield. Use of naphthylamines in this reaction sequence yields various fluorescent substances with λfl at ca. 630 nm. Copyright
- Riepl, Herbert M.,Urmann, Corinna
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p. 1461 - 1477
(2012/10/08)
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- Acylideneoxoindoles: A new class of reversible inhibitors of human transglutaminase 2
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Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had Ki values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals.
- Kl?ck, Cornelius,Jin, Xi,Choi, Kihang,Khosla, Chaitan,Madrid, Peter B.,Spencer, Andrew,Raimundo, Brian C.,Boardman, Paul,Lanza, Guido,Griffin, John H.
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supporting information; experimental part
p. 2692 - 2696
(2011/06/20)
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- Spectroelectrochemistry of solid indirubin and its sulfonated form
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Electrochemical processes of solid indirubin and its sulfonated form were comparatively studied in aqueous buffers by cyclic voltammetry and long-path-length thin-layer UV-vis spectroelectrochemistry, using a carbon paste working electrode with or without indirubin particles attached. The two forms of indirubin gave similar voltammetric features as well as main reaction products. Alkaline pH of electrolyte generally had a negative effect on both the reaction systems, compared with the acidic pH. Electro-reduction of both indirubins produced their leuco forms, which can be oxidized back to the initial reactants by oxygen. In the alkaline buffers the leuco-indirubin (not sulfonated) may form aggregates with poor solubility and poor electrochemical reactivity. Electro-oxidation of both indirubins led to the irreversible formation of isatin (sulfonated or not). An EC and ECE mechanisms are proposed for the reduction and the oxidation, respectively, of indirubin in two forms. The combination of solid state and solution phase spectroelectrochemistry shows the advantage of providing multidimensional information for reaction mechanism determination.
- Hu, Xiao-Wei,He, Jian-Bo,You, Ya-Hua,Zhang, Ying-Meng,Zhang, Shi-Liang
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body text
p. 1219 - 1226
(2011/04/19)
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- Altering the regioselectivity of cytochrome P450 BM-3 by saturation mutagenesis for the biosynthesis of indirubin
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Engineering the regioselectivity of enzymes to fulfill application needs is an important goal of protein engineering. To create biocatalysts suitable for the biosynthesis of indirubin (a drug for chronic myelogenous leukemia and a novel promising anticancer agent), cytochrome P450 BM-3 was engineered by site-directed saturation mutagenesis at position D168 to alter its hydroxylation regioselectivity towards indole. One mutant, D168W, was created. It primarily produces indirubin (～90%) whereas the parent enzyme primarily forms indigo (～85%). Docking calculations showed that the mutation altered the orientation of indole, and that the C-2 of the indole pyrrole ring was closer to the heme iron of P450 BM-3 than the C-3. The mutation possibly shifted the hydroxylation preference of P450 BM-3 for indole from the C-3 to C-2, which may be responsible for the reversal of distribution of the product yield. This mutant yielded high-purity indirubin and may be a good starting point for the biosynthesis of indirubin.
- Hu, Sheng,Huang, Jun,Mei, Lehe,Yu, Qing,Yao, Shanjing,Jin, Zhihua
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experimental part
p. 29 - 35
(2010/12/20)
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- Synthesis and structure-activity relationships of novel indirubin derivatives as potent anti-proliferative agents with CDK2 inhibitory activities
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Indirubin, an active ingredient of a traditional Chinese recipe Danggui Longhui Wan, has been known as a CDK inhibitor competing with ATP for binding to the catalytic site of cyclin-dependent kinases (CDKs). Since CDKs, a group of serine/threonine kinases forming active heterodimeric complexes with cyclins, are key regulators of the cell cycle regulation, therapeutic interventions targeting CDKs have been stimulated for the treatment of proliferative diseases, such as cancer, psoriasis, and for the prevention of chemotherapy-associated side effects, such as alopecia. A series of novel indirubin analogs was synthesized and evaluated for anti-proliferative and CDK2 inhibitory activities. Among the indirubin derivatives tested in the growth inhibitions against several human cancer cell lines, 5-nitro, halide, and bulky group containing acylamino substituted analogs showed high anti-proliferative effects. Selected analogs showing potent anti-proliferative activities were evaluated further in the CDK2 enzyme assay, which resulted in the discovery of potent CDK2 inhibitors.
- Moon, Myoung Ju,Lee, Sang Kook,Lee, Jong-Won,Song, Woo Keun,Kim, Si Wouk,Kim, Jae Il,Cho, Chunghee,Choi, Soo Jeong,Kim, Yong-Chul
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p. 237 - 246
(2007/10/03)
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- Enhancing effect of indirubin derivatives on 1,25-dihydroxyvitamin D3- and all-trans retinoic acid-induced differentiation of HL-60 leukemia cells
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The induction of differentiation represents a new and promising approach to cancer therapy, well illustrated by the treatment of acute promyelocytic leukemia (APL) with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid (ATRA). Using combinations of low, nontoxic concentrations of either 1,25-(OH)2D3 or ATRA and differentiation-enhancing chemicals, adverse effects such as hypercalcemic effects have been ameliorated, and long-term survival has been improved. Indirubin has been demonstrated to exert anti-leukemic effects in cases of chronic myelocytic leukemia. Previously, we synthesized a series of indirubin derivatives and evaluated their anti-proliferative properties against cancer cells. In this study, we determined the enhancing activities of these derivatives on 1,25-(OH)2D3- and ATRA-induced differentiation of human promyelocytic leukemia HL-60 cells. Importantly, some of these derivatives were found to synergistically enhance the differentiation of HL-60 cells in a concentration-dependent manner when coupled with low doses of either 1,25-(OH)2D3 or ATRA. The ability of indirubin derivatives to enhance the differentiation potential of 1,25-(OH)2D3 or ATRA may improve the ultimate outcomes of APL therapy.
- Kim, Seung Hyun,Kim, Si-Wouk,Choi, Soo Jeong,Kim, Yong-Chul,Kim, Tae Sung
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p. 6752 - 6758
(2007/10/03)
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- Identification of broad specificity P450CAM variants by primary screening against indole as substrate
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High-throughput screening of cytochrome P450CAM libraries, for their ability to oxidise indole to indigo and indirubin, has resulted in the identification of variants with activity towards the structurally unrelated substrate diphenylmethane. The Royal Society of Chemistry 2005.
- Celik, Ayhan,Speight, Robert E.,Turner, Nicholas J.
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p. 3652 - 3654
(2007/10/03)
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- INDIRUBIN DERIVATIVES HAVING ANTICANCER PROPERTY AGAINST HUMAN CANCER CELL ME
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The present invention relates to an indirubin derivative having anticancer property by inhibiting cell proliferation as to human cancer cell line. More particularly, this invention provides the synthesis of indirubin derivative known as CDK(Cyclin-dependent kinase) inhibitor. Further, inhibition activity of proliferation as to human cancer cell line and apoptosis against induced-differentiation of said indirubin derivative are researched to develop a novel indirubin derivative having efficacious anticancer properties as to various human cell lines.
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Page/Page column 6
(2008/06/13)
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- INDIRUBIN-TYPE COMPOUNDS, COMPOSITIONS, AND METHODS FOR THEIR USE
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Compounds and compositions including 6-bromo-indirubin, 5-amino-indirubin and N-methyl-indirubins and related indirubin derivatives are provided that are useful as selective modulators of glycogen synthase kinase-3, cyclin-dependent protein kinases or aryl hydrocarbon receptors. Methods of inhibiting or modulating cell growth or cell cycling are provided using the compounds of the invention. In other aspects, compounds and methods for the treatment of protozoan-mediated diseases, Alzheimer's disease and diabetes are provided.
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Page/Page column 39
(2008/06/13)
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- Structural Basis for the Synthesis of Indirubins as Potent and Selective Inhibitors of Glycogen Synthase Kinase-3 and Cyclin-Dependent Kinases
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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.
- Polychronopoulos, Panagiotis,Magiatis, Prokopios,Skaltsounis, Alexios-Leandros,Myrianthopoulos, Vassilios,Mikros, Emmanuel,Tarricone, Aldo,Musacchio, Andrea,Roe, S. Mark,Pearl, Laurence,Leost, Maryse,Greengard, Paul,Meijer, Laurent
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p. 935 - 946
(2007/10/03)
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- Use of cell membrane penetrating indigoid bisindole derivatives
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The present invention relates to the use of cell membrane penetrating indigoid bisindole derivatives for the manufacture of a medicament for the treatment of human solid cancers.
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Page column 3-4
(2008/06/13)
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- Identification of an indigo precursor from leaves of Isatis tinctoria (Woad)
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Indole is presumably a product of indole-3-glycerol phosphate catabolism in Isatis tinctoria. It is oxidized into indoxyl and stored in young leaves as indigo precursor. Further oxidation and dimerization of indoxyl produces indigoid pigments. In this work, we describe an HPLC method dedicated to the identification and quantification of indigoid pigments (indigo, indirubin, isoindigo and isoindirubin) and indigo precursors produced in I tinctoria (Woad). This work, carried out with two cultivars of I tinctoria, has confirmed that the quantity of indigo precursors is dependent on the species and the harvest period. In addition we have shown for the first time that young leaves of I. tinctoria, harvested in June contained a new indigo precursor in addition to isatan B (indoxyl-5-ketogluconate) and indican (indoxyl-β-D-glucoside). We suggest the name isatan C for this new indigo precursor in I. tinctoria. Its chemical characteristics point to an dioxindole ester with PM of 395. We have shown that isatan C reacts with isatan B increasing the red pigment production.
- Maugard, Thierry,Enaud, Estelle,Choisy, Patrick,Legoy, Marie Dominique
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p. 897 - 904
(2007/10/03)
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- Chemical constituents of two oriental orchids, Calanthe discolor and C. liukiuensis: Precursor indole glycoside of tryptanthrin and indirubin
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Two indole glycosides, calanthoside and glucoindican, were isolated from two oriental orchids, Calanthe discolor LINDL. and C. liukiuensis SCHLTR., together with calaphenanthreol, calaliukiuenoside, and bioactive known alkaloids, tryptanthrin, indirubin, and isatin. The structures of calanthoside, glucoindican, calaphenanthreol, and calaliukiuenoside were determined on the basis of physicochemical and chemical evidence. Furthermore, it was found that enzymatic hydrolysis of calanthoside furnished tryptanthrin as the main product, whereas indirubin and isatin were obtained by acid hydrolysis of calanthoside.
- Murakami, Toshiyuki,Kishi, Akinobu,Sakurama, Tetsuo,Matsuda, Hisashi,Yoshikawa, Masayuki
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p. 957 - 966
(2007/10/03)
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- Directed evolution of the fatty-acid hydroxylase P450 BM-3 into an indole-hydroxylating catalyst
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The self-sufficient cytochrome P450 BM-3 enzyme from Bacillus megaterium catalyzes subterminal hydroxylation of saturated long-chain fatty acids and structurally related compounds. Since the primary structure of P450 BM-3 is homologous to that of mammalian P450 type II, it represents an excellent model for this family of enzymes. During studies on the directed evolution of P450 BM-3 into a medium-chain fatty-acid hydroxylase, several mutants, in particular the triple mutant Phe87Val, Leu 188Gln, Ala74Gly, were observed to hydroxylate indole, producing indigo and indiruhin at a catalytic efficiency of 1365M-1s-1 (kcat=2.73 s-1 and Km,=2.0mM). Both products were unequivocally characterized by NMR and MS analysis. Wild-type P450 BM-3 is incapable to hydroxylate indole. These results demonstrate that an enzyme can be engineered to catalyze the transformation of substrates with structures widely divergent from those of its native substrate.
- Li, Qing-Shan,Schwaneberg, Ulrich,Fischer, Peter,Schmid, Rolf D.
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p. 1531 - 1536
(2007/10/03)
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- Effects of Organic Solvents on Indigo Formation by Pseudomonas sp. strain ST-200 Grown with High Levels of Indole
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The indole tolerance level of Pseudomonas sp. strain ST-200 was 0.25 mg/ml. The level was raised to 4 mg/ml when diphenylmethane was added to the medium to 20% by volume. ST-200 grown in this two-phase culture system containing indole (1 mg/ml) and diphenylmethane (0.2 ml/ml) produced a water-soluble yellow pigment, isatic acid, and two water-insoluble and diphenylmethane-soluble pigments, blue indigo and purple indirubin. The amounts of the water-insoluble pigments corresponded to 0.5% (indigo) and 0.2% (indirubin) of the indole added to the medium. Of the conditions tried, indigo and indirubin were formed only when ST-200 was grown in the two-phase system overlaid with organic solvents with appropriate polarity.
- Doukyu, Noriyuki,Arai, Tomonori,Aono, Rikizo
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p. 1075 - 1080
(2007/10/03)
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- 2-Chloro-3H-indol-3-one and its Reactions with Nucleophiles
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The title compound reacts with N- and S-nucleophiles to form 3-substituted indol-2-ones, but with C-nucleophiles to afford either these or the corresponding 2-substituted indol-3-ones.This dichotomy of behavior is documented and rationalized.
- Katritzky, Alan R.,Fan, Wei-Qiang,Koziol, Anna E.,Palenik, Gus J.
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p. 821 - 828
(2007/10/02)
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