Synthesis of novel 5-substituted indirubins as protein kinases inhibitors

Beauchard, Anne; Ferandin, Yoan; Frere, S. S.; Lozach, Olivier; Blairvacq, Mélina; Meijer, Laurent; Thiéry, Valérie; Besson, Thierry

doi:10.1016/j.bmc.2006.05.036

Cited by 94 publications

(57 citation statements)

References 15 publications

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“…Isatin itself exhibited a range of actions such as CNS-MAO inhibition, sedative, anticonvulsant and anxiogenic activities [1]. Similarly, isatin derivatives are known to possess a wide spectrum of pharmacological properties including anthelmintic, antibacterial, anticonvulsant, antifungal, antineoplastic, antiviral, cysticidal, herbicidal, hypotensive and enzymatic inhibition [1][2][3][4]. Among these, isatins-derived thiosemicarbazones have raised considerable interest [5 -12].…”

Section: Synthesis and Biological Evaluation Of Some New N 4 -Substitmentioning

confidence: 99%

Synthesis and biological evaluation of some new N⁴-substituted isatin-3-thiosemicarbazones

Pervez

Chohan

Ramzan

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Synthesis and Biological Evaluation Of Some New N 4 -Substitmentioning

confidence: 99%

Synthesis and biological evaluation of some new N⁴-substituted isatin-3-thiosemicarbazones

Pervez

Chohan

Ramzan

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Trimethoprim and indirubin-3Ј-oxime 4a were obtained from Sigma Chemical Co. (St. Louis, MO). All other indirubin and tryptanthrin derivatives were synthesized by standard methods (1,12). The analogs of indirubin 1a were prepared by condensation of 3-acetoxy indole with the appropriate isatin derivatives in the presence of sodium carbonate.…”

Section: Tryptanthrins Have Potential As Anti-toxoplasma Infection Thmentioning

confidence: 99%

Inhibition of Toxoplasma gondii by Indirubin and Tryptanthrin Analogs

Krivogorsky¹,

Grundt

Yolken³

et al. 2008

Antimicrob Agents Chemother

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New drugs are needed for treatment of Toxoplasma gondii infections. We tested derivatives of principles found in Isatis indigotica for in vitro efficacy against T. gondii infection. Indirubin-3-oxime analogs showed modest micromolar activity, while tryptanthrin derivatives displayed 50% inhibitory doses in the low nanomolar range. Tryptanthrins have potential as anti-Toxoplasma infection therapeutics.Toxoplasma gondii is an apicomplexan parasite with worldwide distribution. T. gondii infections in humans range from overwhelming infection in neonates and immunocompromised individuals to inapparent infections in immunocompetent hosts. Current medications for the prevention and treatment of Toxoplasma infection are hampered by toxicity and limited efficacy.Our approach to address this drug deficit was to examine natural and synthetic derivatives of principles found in the Chinese medicinal herb Isatis indigotica for the ability to disrupt the in vitro growth of T. gondii. Our primary focus centered around analogs of the components indirubin 1a (Table 1) and tryptanthrin 2a (Table 2) (7). Derivatives of these compounds have been shown to possess activity against several protozoan pathogens. Specifically, both classes of compounds have been shown to inhibit some strains of Leishmania spp. (3, 4; E. Xingi, V. Myrianthopoulos, D. Smirlis, S. Bisti, P. Magiatis, E. Mikros, L. Skaltsounis, and K. Soteriadou, presented at the 3rd COST B22 Annual Congress, Drug Discovery and Development for Parasitic Diseases, Athens, Greece, 2006). In addition, tryptanthrin derivatives have been reported to inhibit Trypanosoma brucei (11) and another apicomplexan parasite, Plasmodium falciparum (2). To our knowledge, there are no reports of the activities of these compounds as inhibitors of T. gondii. Therefore, we examined the ability of derivatives of indirubin and tryptanthrin to inhibit the growth of T. gondii in cell culture.Indirubin-5-sulfonic acid 1c was obtained from Alexis Biochemicals, San Diego, CA. Indirubin-3Ј-oxime-5-sulfonic acid 4c and indirubin derivative E804 6 (9) were purchased from Calbiochem, Darmstadt, Germany. Trimethoprim and indirubin-3Ј-oxime 4a were obtained from Sigma Chemical Co. (St. Louis, MO). All other indirubin and tryptanthrin derivatives were synthesized by standard methods (1, 12). The analogs of indirubin 1a were prepared by condensation of 3-acetoxy indole with the appropriate isatin derivatives in the presence of sodium carbonate. Treatment of 1a with hydroxylamine hydrochloride in pyridine gave the 3Ј-oxime analogs 4 (4a to 4k). The 1-N-acetyl derivative 3 and 3Ј-acetoxy-oxime compounds 5 (5a and 5k) were prepared by treatment of compound 1a or 4a with acetic anhydride. The analogs of tryptanthrin 2a were synthesized from isatoic anhydride and the corresponding isatin derivatives in refluxing toluene with triethylamine as cosolvent.Compounds were tested for in vitro efficacy against T. gondii tachyzoites, using methods which have been described in detail in previous publications (5). Briefly, tes...

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“…For example, 5-substituted indirubins display high inhibitory potency toward various CDKs and GSK-3b. [8,9,14] Among indirubin isomers isolated from marine organisms, the natural product 6-bromoindirubin and its synthetic, more cell-permeable derivative 6-bromoindirubin-3'-oxime also show enhanced selective inhibition of GSK-3 versus CDKs. [15,16] The high inhibitory potency of 5-nitroindirubin-3'-oxime led various research groups to synthesize disubstituted indirubins, namely at positions 5 and 7, thereby possibly combining selectivity and high activity.…”

Section: Introductionmentioning

confidence: 99%

“…[7] This substance and its substituted derivatives are potent inhibitors of several kinases such as glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases (CDKs). [8,9] Phosphorylation of serine, threonine, and tyrosine residues by cellular protein kinases plays an important role in the regulation of various cellular processes. [10] Protein kinases constitute the largest family of human enzymes and are considered to be the largest class amenable to therapeutic intervention by smallmolecule drugs.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Bioactivity of Carbohydrate Derivatives of Indigo, Its Isomers and Heteroanalogues

et al. 2010

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Synthesis of novel 5-substituted indirubins as protein kinases inhibitors

Cited by 94 publications

References 15 publications

Synthesis and biological evaluation of some new N⁴-substituted isatin-3-thiosemicarbazones

Synthesis and biological evaluation of some new N⁴-substituted isatin-3-thiosemicarbazones

Inhibition of Toxoplasma gondii by Indirubin and Tryptanthrin Analogs

Synthesis and Bioactivity of Carbohydrate Derivatives of Indigo, Its Isomers and Heteroanalogues

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Synthesis of novel 5-substituted indirubins as protein kinases inhibitors

Cited by 94 publications

References 15 publications

Synthesis and biological evaluation of some new N4-substituted isatin-3-thiosemicarbazones

Synthesis and biological evaluation of some new N4-substituted isatin-3-thiosemicarbazones

Inhibition of Toxoplasma gondii by Indirubin and Tryptanthrin Analogs

Synthesis and Bioactivity of Carbohydrate Derivatives of Indigo, Its Isomers and Heteroanalogues

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Synthesis and biological evaluation of some new N⁴-substituted isatin-3-thiosemicarbazones

Synthesis and biological evaluation of some new N⁴-substituted isatin-3-thiosemicarbazones