From Tyrian Purple to Kinase Modulators: Naturally Halogenated Indirubins and Synthetic Analogues

Abstract

Indirubins represent a small category of compounds with significant pharmacological activity focusing on the inhibition of protein kinases. A series of derivatives has been developed during the last 15 years aiming the investigation and amelioration of the indirubin scaffold in terms of activity, selectivity, and drug-likeness. The current article focuses on the naturally brominated indirubins present in the famous historic dye of Tyrian purple, attempting to gather all available literature regarding biosynthesis, isolation, and synthesis of related analogues. Halogenated indirubins are by far one of the most important subcategories of indirubins, with its main representatives 6-bromoindirubin (6BI) and 6-bromoindirubin-3′-oxime (6BIO) possessing an increased selectivity against GSK-3. This review attempts to summarize concisely structure/activity relationships among closely related halogenated analogues in terms of protein kinase inhibition and selectivity, while it also focuses on the various biological applications arising from the interactions of halogenated indirubins with molecular targets. Those include effects of halogenated indirubins on stem cells, cardiac, renal, and pancreatic cells, on leukemia and solid tumors, and on neurodegeneration.

Key words

Indirubin - indigo - Tyrian purple - Hexaplex trunculus - Bolinus brandaris - Muricidae - protein kinases - CDKs - GSK-3β - stem cells

• References

• 1 Clark RJH, Cooksey CJ, Daniels MAM, Withnall R. Indigo, woad, and Tyrian Purple: important vat dyes from antiquity to the present. Endeavour 1993; 17: 191-199
• 2 Weston CH. Observations on the manner of manufacturing indigo in the Southern Provinces of India; with some remarks on its chemical changes and combinations. J Franklin I 1829; 8: 233-240
• 3 Doménech A, Doménech-Carbó MT, del Rio MS, Goberna S, Lima E. Evidence of topological indigo/dehydroindigo isomers in maya blue-like complexes prepared from palygorskite and sepiolite. J Phys Chem C 2009; 113: 12118-12131
• 4 Ricketts R. Polygonum tinctorium: contemporary indigo farming and processing in Japan. In: Meijer L, Guyard N, Skaltsounis AL, Eisenbrand G, editors Indirubin, the red shade of indigo. Roscoff, France: Life in Progress Editions; 2006: 147-156
• 5 McGovern PE, Michel RH. Royal purple dye: tracing the chemical origins of the industry. Anal Chem 1985; 57: 1514-1522
• 6 Hoffman RC, Zilber RC, Hoffman RE. NMR spectroscopic study of the Murex trunculus dyeing process. Magn Reson Chem 2010; 48: 892-895
• 7 Van Elslande E, Lecomte S, Le Ho AS. Micro-Raman spectroscopy (MRS) and surface-enhanced Raman scattering (SERS) on organic colourants in archaeological pigment. J Raman Spectrosc 2008; 39: 1001-1006
• 8 March RE, Papanastasiou M, McMahon AW, Allen NS. An investigation of paint from a mural in the church of Sainte Madeleine, Manas, France. J Mass Spectrom 2011; 46: 816-820
• 9 Dupont C. The dog whelk Nucella lapillus and dye extraction activities from the iron age to the middle ages along the Atlantic coast of France. J Island Coastal Archeol 2011; 6: 3-23
• 10 Withnall R, Patel D, Cooksey C, Naegel L. Chemical studies of the purple dye of Purpura pansa . Dyes Hist Archaeol 2003; 19: 109-117
• 11 Wu LM, Yang YP, Zhu ZH. Studies on the active principles of Indigofera tinctoria in the treatment of CML. Comm Chin Herb Med 1979; 9: 6-8
• 12 Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3 specific inhibitor. Nat Med 2004; 10: 55-63
• 13 Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L. Indirubin inhibits glycogen synthase kinase-3 beta and CDK5/p 25, two protein kinases involved in abnormal tau phosphorylation in Alzheimerʼs disease. A property common to most cyclin-dependent kinase inhibitors?. J Biol Chem 2001; 276: 251-260
• 14 Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin dependent kinases. Nat Cell Biol 1999; 1: 60-67
• 15 Myrianthopoulos V, Magiatis P, Ferandin Y, Skaltsounis AL, Meijer L, Mikros E. An integrated computational approach to the phenomenon of potent and selective inhibition of aurora kinases B and C by a series of 7-substituted indirubins. J Med Chem 2007; 50: 4027-4037
• 16 Adachi J, Mori Y, Matsui S, Takigami H, Fujino J, Kitagawa H, Miller 3rd CA, Kato T, Saeki K, Matsuda T. Indirubin and indigo are potent aryl hydrocarbon receptor ligands present in human urine. J Biol Chem 2001; 276: 31475-31478
• 17 Knockaert M, Blondell M, Bach S, Leost M, Elbi C, Hager GL, Nagy SR, Han D, Denison M, Ffrench M, Ryan XP, Magiatis P, Polychronopoulos P, Greengard P, Skaltsounis L, Meijer L. Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins. Oncogene 2004; 23: 4400-4412
• 18 Grothaus PG, Cragg GM, Newman DJ. Plant natural products in anticancer drug discovery. Curr Org Chem 2010; 14: 1781-1791
• 19 Schunck E. On the formation of indigo-blue. Part I. Mem Manchester Lit Phil Soc Ser 2 1855; 2: 177-208
• 20 Maugard T, Enaud E, Choisy P, Legoy MD. Identification of an indigo precursor from leaves of Isatis tinctoria (Woad). Phytochemistry 2001; 58: 897-904
• 21 Guengerich PF, Martin MV, McCormick WA, Nguyen LP, Glover E, Bradfield CA. Aryl hydrocarbon receptor response to indigoids in vitro and in vivo . Arch Biochem Biophys 2004; 423: 309-316
• 22 Shiao CC, Weng CY, Chuang JC, Huang MS, Chen ZY. Purple urine bag syndrome: a community-based study and literature review. Nephrology (Carlton) 2008; 13: 554-559
• 23 Cooksey CJ. Tyrian purple: 6,6′-dibromoindigo and related compounds. Molecules 2001; 6: 736-769
• 24 Oberthür C, Graf H, Hamburger M. The content of indigo precursors in Isatis tinctoria leaves–a comparative study of selected accessions and post-harvest treatments. Phytochemistry 2004; 65: 3261-3268
• 25 Oberthür C, Schneider B, Graf H, Hamburger M. The elusive indigo precursors in woad (Isatis tinctoria L.)–identification of the major indigo precursor, isatan A, and a structure revision of isatan B. Chem Biodivers 2004; 1: 174-182
• 26 Chen H-J, Tsao H-H, Lo JG, Chiu K-H, Jen J-F. Supercritical fluid extraction coupled with solvent-less spray collection mode for rapid separation of indirubin and tryptanthrin from Folium Isatidis. Sep Sci Technol 2011; 46: 972-997
• 27 Friedländer P. Über den Farbstoff des antiken Purpurs aus Murex brandaris . Chem Ber 1909; 42: 765-770
• 28 Karapanagiotis I, de Villemereuil V, Magiatis P, Polychronopoulos P, Vougogiannopoulou K, Skaltsounis AL. Identification of the coloring constituents of four natural indigoid dyes. J Liq Chromatogr R T 2006; 29: 1491-1502
• 29 Baker JT, Sutherland MD. Pigments of marine animals. VIII. Precursors of 6,6′-dibromoindigotin (Tyrian Purple) from the mollusc Dicathais orbita gmelin. Tetrahedron Lett 1968; 1: 43-46
• 30 Baker JT, Duke CC. Isolation of choline and choline ester salts of tyrindoxyl sulphate from the marine molluscs Dicathais orbita and Mancinella keineri . Tetrahedron Lett 1976; 15: 1233-1234
• 31 Baker JT. Tyrian Purple: an ancient dye, a modern problem. Endeavour 1976; 33: 11-17
• 32 Fujise Y, Miwa K, Ito S. Structure of tyriverdin, the intermediate precursor of Tyrian purple. Chem Lett 1980; 6: 631-632
• 33 López Chávez FJ, Ríos Chávez P, Oyama K. Brominated precursors of Tyrian purple (C.I. Natural Violet 1) from Plicopurpura pansa, Plicopurpura columellaris, and Plicopurpura patula . Dyes Pigments 2009; 83: 7-13
• 34 Fouquet H, Bielig H-J. Biological precursors and genesis of tyrian-purple. Angew Chem Int Ed 1971; 10: 816-817
• 35 Westley C, Benkendorff K. Sex-specific Tyrian purple genesis: precursor and pigment distribution in the reproductive system of the marine mollusc, Dicathais orbita . J Chem Ecol 2008; 34: 44-56
• 36 Benkendorff K, Bremner JB, Davies AR. Tyrian Purple precursors in the egg masses of the australian muricid Dicathais orbita: a possible defensive role. J Chem Ecol 2000; 26: 1037-1050
• 37 Benkendorff K, Bremner JB, Davies AR. Indole derivatives from the egg masses of Muricid molluscs. Molecules 2001; 6: 70-78
• 38 Magiatis P, Skaltsounis AL. From Hexaplex trunculus to new kinase inhibitory indirubins. In: Meijer L, Guyard N, Skaltsounis AL, Eisenbrand G, editors Indirubin, the red shade of indigo. Roscoff, France: Life in Progress Editions; 2006: 147-156
• 39 Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Knockaert M, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R, Crovace C, Tarricone C, Musacchio A, Roe SM, Pearl L, Greengard P. GSK-3-selective inhibitors derived from Tyrian purple indirubins. Chem Biol 2003; 10: 1255-1266
• 40 Puchalska M, Połeć-Pawlak K, Zadrozna I, Hryszko H, Jarosz M. Identification of indigoid dyes in natural organic pigments used in historical art objects by high-performance liquid chromatography coupled to electrospray ionization mass spectrometry. J Mass Spectrom 2004; 39: 1441-1449
• 41 Nowik W, Marcinowska R, Kusyk K, Cardon D, Trojanowicz M. High performance liquid chromatography of slightly soluble brominated indigoids from Tyrian purple. J Chromatogr A 2011; 1218: 1244-1252
• 42 Benkendorff K, Westley CB, Gallardo CS. Observations on the production of purple pigments in the egg capsules, hypobranchial and reproductive glands from seven species of Muricidae (Gastropoda: Mollusca). Invertebr Reprod Dev 2004; 46: 93-102
• 43 Edwards V, Benkendorff K, Young F. Marine compounds selectively induce apoptosis in female reproductive cancer cells but not in primary-derived human reproductive granulosa cells. Mar Drugs 2012; 10: 64-83
• 44 Westley CB, McIver CM, Abbott CA, Le Leu RK, Benkendorff K. Enhanced acute apoptotic response to azoxymethane-induced DNA damage in the rodent colonic epithelium by Tyrian purple precursors: a potential colorectal cancer chemopreventative. Cancer Biol Ther 2010; 9: 371-379
• 45 Bayer A. Ueber die Verbindungen der Indigogruppe. Chem Ber 1883; 16: 2188-2204
• 46 Russel GA, Kaupp G. Oxidation of carbanions. IV. Oxidation of indoxyl to indigo in basic solution. J Am Chem Soc 1969; 91: 3851-3859
• 47 Clarck RJH, Cooksey CJ. Bromoindirubins: the synthesis and properties of minor components of Tyrian purple and the composition of the colorant from Nucella lapillus . J Soc Dyers Colour 1997; 113: 316-321
• 48 Sandmeyer T. Ueber Isonitrosoacetanilide und deren Kondensation zu Isatinen. Helv Chim Acta 1919; 2: 234-242
• 49 Zhang A, Yu M, Lan T, Liu Z, Mao Z. Novel synthesis of 4- or 6-substituted indirubin derivatives. Synth Commun 2010; 40: 3125-3134
• 50 Tanoue Y, Ikoma Y, Kai N, Nagai T. Synthesis of halogenoindirubins. J Heterocyclic Chem 2009; 46: 1016-1018
• 51 Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A, Musacchio A, Roe SM, Pearl L, Leost M, Greengard P, Meijer L. Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J Med Chem 2004; 47: 935-946
• 52 Saito H, Tabata K, Hanada S, Kanda Y, Suzuki T, Miyairi S. Synthesis of methoxy- and bromo-substituted indirubins and their activities on apoptosis induction in human neuroblastoma cells. Bioorg Med Chem Lett 2011; 21: 5370-5373
• 53 Beauchard A, Laborie H, Rouillard H, Lozach O, Ferandin Y, Le Guével R, Guguen-Guillouzo C, Meijer L, Besson T, Thiéry V. Synthesis and kinase inhibitory activity of novel substituted indigoids. Bioorg Med Chem 2009; 17: 6257-6263
• 54 Beauchard A, Ferandin Y, Frère S, Lozach O, Blairvacq M, Meijer L, Thiéry V, Besson T. Synthesis of novel 5-substituted indirubins as protein kinases inhibitors. Bioorg Med Chem 2006; 14: 6434-6443
• 55 Park EJ, Choi SJ, Kim YC, Lee SH, Park SW, Lee SK. Novel small molecule activators of beta-catenin-mediated signaling pathway: structure-activity relationships of indirubins. Bioorg Med Chem Lett 2009; 19: 2282-2284
• 56 Moon MJ, Lee SK, Lee JW, Song WK, Kim SW, Kim JI, Cho C, Choi SJ, Kim YC. Synthesis and structure-activity relationships of novel indirubin derivatives as potent anti-proliferative agents with CDK2 inhibitory activities. Bioorg Med Chem 2006; 14: 237-246
• 57 Choi SJ, Lee JE, Jeong SY, Im I, Lee SD, Lee EJ, Lee SK, Kwon SM, Ahn SG, Yoon JH, Han SY, Kim JI, Kim YC. 5-5′-substituted indirubin-3′-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity. J Med Chem 2010; 54: 3696-3706
• 58 Choi SJ, Moon MJ, Lee SD, Choi SU, Han SY, Kim YC. Indirubin derivatives as potent FLT3 inhibitors with anti-proliferative activity of acute myeloid leukemic cells. Bioorg Med Chem Lett 2010; 20: 2033-2037
• 59 Vougogiannopoulou K, Ferandin Y, Bettayeb K, Myrianthopoulos V, Lozach O, Fan Y, Johnson CH, Magiatis P, Skaltsounis AL, Mikros E, Meijer L. Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase − 3 alter circadian period. J Med Chem 2008; 51: 6421-6431
• 60 Jautelat R, Brumby T, Schäfer M, Briem H, Eisenbrand G, Schwahn S, Krüger M, Lücking U, Prien O, Siemeister G. From the insoluble dye indirubin towards highly active, soluble CDK2-inhibitors. Chembiochem 2005; 6: 531-540
• 61 Ferandin Y, Bettayeb K, Kritsanida M, Lozach O, Polychronopoulos P, Magiatis P, Skaltsounis AL, Meijer L. 3′-Substituted 7-halogenoindirubins, a new class of cell death inducing agents. J Med Chem 2006; 49: 4638-4649
• 62 Libnow S, Methling K, Hein M, Michalik D, Harms M, Wende K, Flemming A, Köckerling M, Reinke H, Bednarski PJ, Lalk M, Langer P. Synthesis of indirubin-N′-glycosides and their anti-proliferative activity against human cancer cell lines. Bioorg Med Chem 2008; 16: 5570-5583
• 63 Libnow S, Hein M, Langer P. The first N-glycosylated indoxyls and their application to the synthesis of indirubin-N-glycosides (purple sugars). Synlett 2009; 2009: 221-224
• 64 Kritsanida M, Magiatis P, Skaltsounis AL, Peng Y, Li P, Wennogle LP. Synthesis and antiproliferative activity of 7-azaindirubin-3′-oxime, a 7-aza isostere of the natural indirubin pharmacophore. J Nat Prod 2009; 72: 2199-2202
• 65 Wang ZH, Li WY, Li FL, Zhang L, Hua WY, Cheng JC, Yao QZ. Synthesis and antitumor activity of 7-azaindirubin. Chin Chem Lett 2009; 20: 542-544
• 66 Cheng X, Rasqué P, Vatter S, Merz KH, Eisenbrand G. Synthesis and cytotoxicity of novel indirubin-5-carboxamides. Bioorg Med Chem 2010; 18: 4509-4515
• 67 Schwartz PA, Murray BW. Protein kinase biochemistry and drug discovery. Bioorg Chem 2011; 39: 192-210
• 68 Cohen P. Protein kinases–the major drug targets of the twenty-first century?. Nat Rev Drug Discov 2002; 1: 309-315
• 69 Hunter T, Cooper JA. Protein-tyrosine kinases. Annu Rev Biochem 1985; 54: 897-930
• 70 Xingi E, Smirlis D, Myrianthopoulos V, Magiatis P, Grant KM, Meijer L, Mikros E, Skaltsounis AL, Soteriadou K. 6-Br-5-methylindirubin-3′-oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: exploitation of GSK-3 for treating leishmaniasis. Int J Parasitol 2009; 39: 1289-1303
• 71 Ribas J, Bettayeb K, Ferandin Y, Knockaert M, Garrofé-Ochoa X, Totzke F, Schächtele C, Mester J, Polychronopoulos P, Magiatis P, Skaltsounis AL, Boix J, Meijer L. 7-Bromoindirubin-3′-oxime induces caspase-independent cell death. Oncogene 2006; 25: 6304-6318
• 72 Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-1934
• 73 Norbury C, Nurse P. Animal cell cycles and their control. Annu Rev Biochem 1992; 61: 441-470
• 74 Cicenas J, Valius M. The CDK inhibitors in cancer research and therapy. J Cancer Res Clin Oncol 2011; 137: 1409-1418
• 75 Galons H, Oumata N, Meijer L. Cyclin-dependent kinase inhibitors: a survey of recent patent literature. Expert Opin Ther Pat 2010; 20: 377-404
• 76 Rizzolio F, Tuccinardi T, Caligiuri I, Lucchetti C, Giordano A. CDK inhibitors: from the bench to clinical trials. Curr Drug Targets 2010; 11: 279-290
• 77 Knockaert M, Greengard P, Meijer L. Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci 2002; 23: 417-425
• 78 Lim AC, Qi RZ. Cyclin-dependent kinases in neural development and degeneration. J Alzheimers Dis 2003; 5: 329-335
• 79 Martinez A, Castro A, Dorronsoro I, Alonso M. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev 2002; 22: 373-384
• 80 Boutajangout A, Sigurdsson EM, Krishnamurthy PK. Tau as a therapeutic target for Alzheimerʼs disease. Curr Alzheimer Res 2011; 8: 666-677
• 81 Huang H-C, OʼBrien WT, Klein PS. Targeting glycogen synthase kinase-3 in Alzheimerʼs disease. Drug Discov Today Ther Strateg 2006; 3: 613-619
• 82 Koistinaho J, Malm T, Goldsteins G. Glycogen synthase kinase-3β: a mediator of inflammation in Alzheimerʼs disease?. Int J Alzheimers Dis 2011; 2011: 129753
• 83 Picchini AM, Manji HK, Gould TD. GSK-3 and neurotrophic signaling: Novel targets underlying the pathophysiology and treatment of mood disorders?. Drug Discov Today Dis Mech 2004; 1: 419-428
• 84 Freyberg Z, Ferrando SJ, Javitch JA. Roles of the Akt/GSK-3 and Wnt signaling pathways in schizophrenia and antipsychotic drug action. Am J Psychiatry 2010; 167: 388-396
• 85 Hoeppner LH, Secreto FJ, Westendorf JJ. Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets 2009; 13: 485-496
• 86 Ougolkov AV, Billadeau DD. Targeting GSK-3: a promising approach for cancer therapy?. Future Oncol 2006; 2: 91-100
• 87 Hardt SE, Sadoshima J. Glycogen synthase kinase-3beta: a novel regulator of cardiac hypertrophy and development. Circ Res 2002; 90: 1055-1063
• 88 Phukan S, Babu VS, Kannoji A, Hariharan R, Balaji VN. GSK3beta: role in therapeutic landscape and development of modulators. Br J Pharmacol 2010; 160: 1-19
• 89 GSK-3 inhibitor IX (361550) product details, specifications and data sheets. http://www.merckmillipore.com/greece/life-science-research/gsk-3-inhibitor-ix/EMD_BIO-361550/p_R66b.s1LTrMAAAEWx2EfVhTm
• 90 Han S-Y, Ahn JH, Shin CY, Choi SU. Effects of indirubin derivatives on the FLT3 activity and growth of acute myeloid leukemia cell lines. Drug Develop Res 2010; 71: 221-227
• 91 Luo C, Laaja P. Inhibitors of JAKs/STATs and the kinases: a possible new cluster of drugs. Drug Discov Today 2004; 9: 268-275
• 92 Zahler S, Tietze S, Totzke F, Kubbutat M, Meijer L, Vollmar AM, Apostolakis J. Inverse in silico screening for identification of kinase inhibitor targets. Chem Biol 2007; 14: 1207-1214
• 93 Forde JE, Dale TC. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci 2007; 64: 1930-1944
• 94 Toledo EM, Colombres M, Inestrosa NC. Wnt signaling in neuroprotection and stem cell differentiation. Prog Neurobiol 2008; 86: 281-296
• 95 Yao H, Ashihara E, Maekawa T. Targeting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin Ther Targets 2011; 15: 873-887
• 96 Schnitzer SE, Schmid T, Zhou J, Eisenbrand G, Brüne B. Inhibition of GSK3beta by indirubins restores HIF-1alpha accumulation under prolonged periods of hypoxia/anoxia. FEBS Lett 2005; 579: 529-533
• 97 Sinha D, Wang Z, Ruchalski KL, Levine JS, Krishnan S, Lieberthal W, Schwartz JH, Borkan SC. Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors. Am J Physiol Renal Physiol 2005; 288: F703-F713
• 98 Lee MJ, Kim MY, Mo JS, Ann EJ, Seo MS, Hong JA, Kim YC, Park HS. Indirubin-3′-monoxime, a derivative of a Chinese anti-leukemia medicine, inhibits Notch1 signaling. Cancer Lett 2008; 265: 215-225
• 99 Yoon JH, Kim SA, Kwon SM, Park JH, Park HS, Kim YC, Yoon JH, Ahn SG. 5′-Nitro-indirubinoxime induces G1 cell cycle arrest and apoptosis in salivary gland adenocarcinoma cells through the inhibition of Notch-1 signaling. Biochim Biophys Acta 2010; 1800: 352-358
• 100 Aggarwal BB, Sethi G, Ahn KS, Sandur SK, Pandey MK, Kunnumakkara AB, Sung B, Ichikawa H. Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. Ann NY Acad Sci 2006; 1091: 151-169
• 101 Song L, Turkson J, Karras JG, Jove R, Haura EB. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 2003; 22: 4150-4165
• 102 Zhang X, Song Y, Wu Y, Dong Y, Lai L, Zhang J, Lu B, Dai F, He L, Liu M, Yi Z. Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int J Cancer 2011; 129: 2502-2511
• 103 Schwaiberger AV, Heiss EH, Cabaravdic M, Oberan T, Zaujec J, Schachner D, Uhrin P, Atanasov AG, Breuss JM, Binder BR, Dirsch VM. Indirubin-3′-monoxime blocks vascular smooth muscle cell proliferation by inhibition of signal transducer and activator of transcription 3 signaling and reduces neointima formation in vivo . Arterioscler Thromb Vasc Biol 2010; 30: 2475-2481
• 104 Menschikowski M, Hagelgans A, Hempel U, Siegert G. Glycogen synthase kinase-3beta negatively regulates group IIA phospholipase A2 expression in human aortic smooth muscle and HepG2 hepatoma cells. FEBS Lett 2004; 577: 81-86
• 105 Beurel E, Jope RS. Differential regulation of STAT family members by glycogen synthase kinase-3. J Biol Chem 2008; 283: 21934-21944
• 106 Kawakami F, Yamaguchi A, Suzuki K, Yamamoto T, Ohtsuki K. Biochemical characterization of phospholipids, sulfatide and heparin as potent stimulators for autophosphorylation of GSK-3beta and the GSK-3beta-mediated phosphorylation of myelin basic protein in vitro . J Biochem 2008; 143: 359-367
• 107 Gu YC, Li GL, Yang YP, Fu JP, Li CZ. Synthesis of some halogenated indirubin derivatives. Acta Pharmaceutica Sinica 1989; 24: 629-632
• 108 Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble MEM. Inhibitor binding to active and inactive CDK2: the crystal structure of CDK2-cyclin A/indirubin-5-sulfonate. Structure 2001; 9: 389-397
• 109 Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M. Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. J Mol Biol 2003; 333: 393-407
• 110 Lather V, Kristam R, Saini JS, Kristam R, Karthikeyan NA, Balaji VN. QSAR models for prediction of glycogen synthase kinase-3β inhibitory activity derivatives. QSAR Comb Sci 2008; 27: 718-728
• 111 Toledo EM, Colombres M, Inestrosa NC. Wnt signaling in neuroprotection and stem cell differentiation. Prog Neurobiol 2008; 86: 281-296
• 112 Sineva GS, Pospelov VA. Inhibition of GSK3beta enhances both adhesive and signalling activities of beta-catenin in mouse embryonic stem cells. Biol Cell 2010; 102: 549-560
• 113 Ko KH, Holmes T, Palladinetti P, Song E, Nordon R, OʼBrien TA, Dolnikov A. GSK-3β inhibition promotes engraftment of ex vivo-expanded hematopoietic stem cells and modulates gene expression. Stem Cells 2011; 29: 108-118
• 114 Ogawa K, Nishinakamura R, Iwamatsu Y, Shimosato D, Niwa H. Synergistic action of Wnt and LIF in maintaining pluripotency of mouse ES cells. Biochem Biophys Res Commun 2006; 343: 159-166
• 115 Cartwright P, McLean C, Sheppard A, Rivett D, Jones K, Dalton S. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 2005; 132: 885-896
• 116 Holmes T, OʼBrien TA, Knight R, Lindeman R, Shen S, Song E, Symonds G, Dolnikov A. Glycogen synthase kinase-3beta inhibition preserves hematopoietic stem cell activity and inhibits leukemic cell growth. Stem Cells 2008; 26: 1288-1297
• 117 Jiang J, Zhao M, Zhang A, Yu M, Lin X, Wu M, Wang X, Lu H, Zhu S, Yu Y, Mao Z, Han W. Characterization of a GSK-3 inhibitor in culture of human cord blood primitive hematopoietic cells. Biomed Pharmacother 2010; 64: 482-486
• 118 Manceur AP, Tseng M, Holowacz T, Witterick I, Weksberg R, McCurdy RD, Warsh JJ, Audet J. Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors. Exp Cell Res 2011; 317: 2086-2098
• 119 Krause U, Harris S, Green A, Ylostalo J, Zeitouni S, Lee N, Gregory CA. Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy. Proc Natl Acad Sci USA 2010; 107: 4147-4152
• 120 Wang FS, Ko JY, Weng LH, Yeh DW, Ke HJ, Wu SL. Inhibition of glycogen synthase kinase-3beta attenuates glucocorticoid-induced bone loss. Life Sci 2009; 85: 685-692
• 121 Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinricks CS, Yu Z, Wresinski C, Boni A, Cassard L, Garvin LM, Paulos CH, Muranski P, Restifo NP. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat Med 2009; 15: 808-813
• 122 Zaragosi LE, Wdziekonski B, Fontaine C, Villageois P, Peraldi P, Dani C. Effects of GSK3 inhibitors on in vitro expansion and differentiation of human adipose-derived stem cells into adipocytes. BMC Cell Biol 2008; 9: 11
• 123 Lluis F, Pedone E, Pepe S, Cosma MP. Periodic activation of Wnt/beta-catenin signaling enhances somatic cell reprogramming mediated by cell fusion. Cell Stem Cell 2008; 3: 493-507
• 124 Ullmann U, Gilles C, De Rycke M, Van de Velde H, Sermon K, Liebaers I. GSK-3-specific inhibitor-supplemented hESC medium prevents the epithelial-mesenchymal transition process and the up-regulation of matrix metalloproteinases in hESCs cultured in feeder-free conditions. Mol Hum Reprod 2008; 14: 169-179
• 125 Ikonomou L, Geras-Raaka E, Raaka BM, Gershengorn MC. β-catenin signaling in mesenchymal islet-derived precursor cells. Cell Prolif 2008; 41: 474-491
• 126 Umehara H, Kimura T, Ohtsuka S, Nakamura T, Kitajima K, Ikawa M, Okabe M, Niwa H, Nakano T. Efficient derivation of embryonic stem cells by inhibition of glycogen synthase kinase-3. Stem Cells 2007; 25: 2705-2711
• 127 Yang W, Wei W, Shi C, Zhu J, Ying W, Shen Y, Ye X, Fang L, Duo S, Che J, Shen H, Ding S, Deng H. Pluripotin combined with leukemia inhibitory factor greatly promotes the derivation of embryonic stem cell lines from refractory strains. Stem Cells 2009; 27: 383-389
• 128 Doungpunta J, Sathi A, Sathanawongs A, Jarujinda Y, Oranratnachai A. Fivefold increase in derivation rates of mouse embryonic stem cells after supplementation of the media with multiple factors. Theriogenology 2009; 72: 232-242
• 129 Wen J, Liu J, Song G, Liu L, Tang B, Li Z. Effects of 6-bromoindirubin-3′-oxime on the maintenance of pluripotency of porcine embryonic germ cells in combination with stem cell factor, leukemia inhibitory factor and fibroblast growth factor. Reproduction 2010; 139: 1039-1046
• 130 Sato H, Amagai K, Shimizukawa R, Tamai Y. Stable generation of serum- and feeder-free embryonic stem cell-derived mice with full germline-competency by using a GSK3 specific inhibitor. Genesis 2009; 47: 414-422
• 131 Ribas J, Yuste VJ, Garrofé-Ochoa X, Meijer L, Esquerda JE, Boix J. 7-Bromoindirubin-3′-oxime uncovers a serine protease-mediated paradigm of necrotic cell death. Biochem Pharmacol 2008; 76: 39-52
• 132 Nam S, Buettner R, Turkson J, Kim D, Cheng JQ, Muehlbeyer S, Hippe F, Vatter S, Merz KH, Eisenbrand G, Jove R. Indirubin derivatives inhibit Stat3 signaling and induce apoptosis in human cancer cells. Proc Natl Acad Sci USA 2005; 102: 5998-6003
• 133 Liu L, Nam S, Tian Y, Wu J, Wang Y, Scuto A, Polychronopoulos P, Magiatis P, Skaltsounis L, Jove R. 6-Bromoindirubin-3′-oxime inhibits JAK/STAT3 signaling and induces apoptosis in human melanoma cells. Cancer Res 2011; 71: 3972-3979
• 134 Chebel A, Kagialis-Girard S, Catallo R, Chien WW, Mialou V, Domenech C, Badiou C, Tigaud I, Ffrench M. Indirubin derivatives inhibit malignant lymphoid cell proliferation. Leuk Lymphoma 2009; 50: 2049-2060
• 135 Song EY, Palladinetti P, Klamer G, Ko KH, Lindeman R, OʼBrien TA, Dolnikov A. Glycogen synthase kinase–3β inhibitors suppress leukemia cell growth. Exp Hematol 2010; 38: 908-921 (e1)
• 136 Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature 2008; 455: 1205-1209
• 137 Williams SP, Nowicki MO, Liu F, Press R, Godlewski J, Abdel-Rasoul M, Kaur B, Fernandez SA, Chiocca EA, Lawler SE. Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Cancer Res 2011; 71: 5374-5380
• 138 Bilsland AE, Hoare S, Stevenson K, Plumb J, Gomez-Roman N, Cairney C, Burns S, Lafferty-White K, Roffey J, Hammonds T, Keith WN. Dynamic telomerase gene suppression via network effects of GSK3 inhibition. PLoS ONE 2009; 4: e6459
• 139 Cheng H, Woodgett J, Maamari M, Force T. Targeting GSK-3 family members in the heart: a very sharp double-edged sword. J Mol Cell Cardiol 2011; 51: 607-613
• 140 Tateishi K, Ashihara E, Honsho S, Takehara N, Nomura T, Takahashi T, Ueyama T, Yamagishi M, Yaku H, Matsubara H, Oh H. Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3beta signaling. Biochem Biophys Res Commun 2007; 352: 635-641
• 141 Tseng AS, Engel FB, Keating MT. The GSK-3 inhibitor BIO promotes proliferation in mammalian cardiomyocytes. Chem Biol 2006; 13: 957-963
• 142 Novoyatleva T, Diehl F, van Amerongen MJ, Patra C, Ferrazzi F, Bellazzi R, Engel FB. TWEAK is a positive regulator of cardiomyocyte proliferation. Cardiovasc Res 2010; 85: 681-690
• 143 Qyang Y, Martin-Puig S, Chiravuri M, Chen S, Xu H, Bu L, Jiang X, Lin L, Granger A, Moretti A, Caron L, Wu X, Clarke J, Taketo MM, Laugwitz KL, Moon RT, Gruber P, Evans SM, Ding S, Chien KR. The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway. Cell Stem Cell 2007; 1: 165-179
• 144 Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR. Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 2009; 460: 113-117
• 145 Valerio A, Bertolotti P, Delbarba A, Perego C, Dossena M, Ragni M, Spano P, Carruba MO, De Simoni MG, Nisoli E. Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production. J Neurochem 2011; 116: 1148-1159
• 146 Skardelly M, Gaber K, Schwarz J, Milosevic J. Neuroprotective effects of the beta-catenin stabilization in an oxygen- and glucose-deprived human neural progenitor cell culture system. Int J Dev Neurosci 2011; 29: 543-547
• 147 Barillas R, Friehs I, Cao-Danh H, Martinez JF, del Nido PJ. Inhibition of glycogen synthase kinase – 3β improves tolerance to ischemia in hypertrophied hearts. Ann Thorac Surg 2007; 84: 126-133
• 148 Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med 2007; 13: 324-331
• 149 Lin CL, Wang JY, Huang YT, Kuo YH, Surendran K, Wang FS. Wnt/beta-catenin signaling modulates survival of high glucose-stressed mesangial cells. J Am Soc Nephrol 2006; 17: 2812-2820
• 150 Kuure S, Popsueva A, Jakobson M, Sainio K, Sariola H. Glycogen synthase kinase-3 inactivation and stabilization of beta-catenin induce nephron differentiation in isolated mouse and rat kidney mesenchymes. J Am Soc Nephrol 2007; 18: 1130-1139
• 151 Wang Y, Huang WC, Wang CY, Tsai CC, Chen CL, Chang YT, Kai JI, Lin CF. Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis. Br J Pharmacol 2009; 157: 1004-1013
• 152 Mussmann R, Geese M, Harder F, Kegel S, Andag U, Lomow A, Burk U, Onichtchouk D, Dohrmann C, Austen M. Inhibition of GSK3 promotes replication and survival of pancreatic beta cells. J Biol Chem 2007; 282: 12030-12037
• 153 Itoh T, Kamiya Y, Okabe M, Tanaka M, Miyajima A. Inducible expression of Wnt genes during adult hepatic stem/progenitor cell response. FEBS Lett 2009; 583: 777-781
• 154 Meijer L, Flajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 2004; 25: 471-480
• 155 Lim YW, Yoon SY, Choi JE, Kim SM, Lee HS, Choe H, Lee SC, Kim DH. Maintained activity of glycogen synthase kinase-3beta despite of its phosphorylation at serine-9 in okadaic acid-induced neurodegenerative model. Biochem Biophys Res Commun 2010; 395: 207-212
• 156 Martin L, Magnaudeix A, Esclaire F, Yardin C, Terro F. Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A. Brain Res 2009; 1252: 66-75
• 157 Martin L, Page G, Terro F. Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A preferentially involve GSK3β . Neurochem Int 2011; 59: 235-250
• 158 Martin L, Magnaudeix A, Wilson CM, Yardin C, Terro F. The new indirubin derivative inhibitors of glycogen synthase kinase-3, 6-BIDECO and 6-BIMYEO, prevent tau phosphorylation and apoptosis induced by the inhibition of protein phosphatase-2A by okadaic acid in cultured neurons. J Neurosci Res 2011; 89: 1802-1811
• 159 Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET. Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol 2003; 23: 6027-6036
• 160 Nguyen TB, Lucero GR, Chana G, Hult BJ, Tatro ET, Masliah E, Grant I, Achim CL, Everall IP. HIV Neurobehavioral Research Group. Glycogen synthase kinase-3beta (GSK-3beta) inhibitors AR-A014418 and B6B3O prevent human immunodeficiency virus-mediated neurotoxicity in primary human neurons. J Neurovirol 2009; 15: 434-438
• 161 Meares GP, Mines MA, Beurel E, Eom TY, Song L, Zmijewska AA, Jope RS. Glycogen synthase kinase-3 regulates endoplasmic reticulum (ER) stress-induced CHOP expression in neuronal cells. Exp Cell Res 2011; 317: 1621-1628
• 162 Magiatis P, Polychronopoulos P, Skaltsounis AL, Lozach O, Meijer L, Miller DB, OʼCallaghan JP. Indirubins deplete striatal monoamines in the Intact and MPTP-treated mouse brain and block kainate-induced striatal astrogliosis. Neurotoxicol Teratol 2010; 32: 212-219
• 163 Kim WY, Zhou FQ, Zhou J, Yokota Y, Wang YM, Yoshimura T, Kaibuchi K, Woodgett JR, Anton ES, Snider WD. Essential roles for GSK-3s and GSK-3-primed substrates in neurotrophin induced and hippocampal axon growth. Neuron 2006; 52: 981-996
• 164 Alabed YZ, Pool M, Ong Tone S, Sutherland C, Fournier AE. GSK-3β regulates myelin – dependent axon outgrowth inhibition through CRMP4. J Neurosci 2010; 30: 5635-5643
• 165 Xingi E, Smirlis D, Myrianthopoulos V, Magiatis P, Grant KM, Meijer L, Mikros E, Skaltsounis AL, Soteriadou K. 6-Br-5methylindirubin-3′oxime (5-Me-6-BIO) targeting the leishmanial glycogen synthase kinase-3 (GSK-3) short form affects cell-cycle progression and induces apoptosis-like death: exploitation of GSK-3 for treating leishmaniasis. Int J Parasitol 2009; 39: 1289-1303
• 166 Grant KM, Dunion MH, Yardley V, Skaltsounis AL, Marko D, Eisenbrand G, Croft SL, Meijer L, Mottram JC. Inhibitors of Leishmania mexicana CRK3 cyclin-dependent kinase: chemical library screen and antileishmanial activity. Antimicrob Agents Chemother 2004; 48: 3033-3042
• 167 Mahendra A, Vivek K, Parameswaran S, Mohan CG. Homology modeling and atomic level binding study of Leishmania MAPK with inhibitors. J Mol Model 2010; 16: 475-488
• 168 Krivogorsky B, Grundt P, Yolken R, Jones-Brando L. Inhibition of Toxoplasma gondii by indirubin and tryptanthrin analogs. Antimicrob Agents Chemother 2008; 52: 4466-4469
• 169 Fabres A, de Andrade CP, Guizzo M, Sorgine MHF, de O Paiva-Silva G, Masuda A, da Silva Vaz I, Logullo C. Effect of GSK-3 activity, enzymatic inhibition and gene silencing by RNAi on tick oviposition and egg hatching. Parasitology 2010; 137: 1-10
• 170 Pohjanvirta R, Tuomisto J. Short-term toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in laboratory animals: effects, mechanisms, and animal models. Pharmacol Rev 1994; 46: 483-549
• 171 Sugihara K, Okayama T, Kitamura S, Yamashita K, Yasuda M, Miyairi S, Minobe Y, Ohta S. Comparative study of aryl hydrocarbon receptor ligand activities of six chemicals in vitro and in vivo . Arch Toxicol 2008; 82: 5-11
• 172 Peter Guengerich F, Martin MV, McCormick WA, Nguyen LP, Glover E, Bradfield CA. Aryl hydrocarbon receptor response to indigoids in vitro and in vivo . Arch Biochem Biophys 2004; 423: 309-316
• 173 Adachi J, Mori Y, Matsui S, Matsuda T. Comparison of gene expression patterns between 2,3,7,8-tetrachlorodibenzo-p-dioxin and a natural arylhydrocarbon receptor ligand, indirubin. Toxicol Sci 2004; 80: 161-169
• 174 Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE, Sherr DH. A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol Chem 2006; 387: 1175-1187
• 175 Puga A, Barnes SJ, Dalton TP, Chang C, Knudsen ES, Maier MA. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. J Biol Chem 2000; 275: 2943-2950
• 176 Korzeniewski N, Wheeler S, Chatterjee P, Duensing A, Duensing S. A novel role of the aryl hydrocarbon receptor (AhR) in centrosome amplification – implications for chemoprevention. Mol Cancer 2010; 9: 153