Phloroglucinolderivate Guttiferon G, Aristoforin und Hyperforin: Inhibitoren der menschlichen Sirtuine SIRT1 und SIRT2

Gey, Claudia; Kyrylenko, Sergiy; Hennig, Lothar; Nguyen, Lien‐Hoa D.; Büttner, Anita; Pham, Hung D.; Giannis, Athanassios

doi:10.1002/ange.200605207

Cited by 17 publications

(11 citation statements)

References 36 publications

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“…[210] In addition to other important bioactivies, [211] 229 was shown to induce promising neurological effects. For example, the antidepressant activity of 229 was attributed to its ability to inhibit neuronal uptake of various neurotransmitters.…”

Section: Neurotrophic Natural Productsmentioning

confidence: 99%

Neurotrophic Natural Products: Chemistry and Biology

2013

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Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project.

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Section: Neurotrophic Natural Productsmentioning

confidence: 99%

Neurotrophic Natural Products: Chemistry and Biology

2013

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“…[5] Further Sirt2 inhibitors have been discovered through a virtual screening approach, but cellular activity and verification of protein hyperacetylation have not been demonstrated. [15][16][17] The sirtuin inhibitor cambinol (3) was discovered from random screening, and for the first time anticancer activity in an animal model could be demonstrated with this compound. [18] Lately, indoles such as 4, with activity down to~0.1 mm have been presented.…”

Section: Introductionmentioning

confidence: 99%

Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free‐Energy Calculations, and Biological Testing

et al. 2008

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NAD+-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors.

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“…Some compounds appear to be rather promising with IC 50 values close to 1 mmol L À1 (or even lower), which is a concentration that might well be achieved as a systemically relevant therapeutic dose. [6][7][8][9][10] Many others, however, exhibit IC 50 values that are clearly higher than 10 mmol L À1 and, in some instances, even approach the millimolar range. [11][12][13][14] In the present study a group of seven indoloquinolizidine derivatives was identified on the basis of functional screening of approximately 11 000 natural-product derived and inspired compounds, which with IC 50 values close to 2 mmol L À1 , inhibited proliferation in different cell lines and increased the amount of apoptotic cells by up to 600 % as compared to the control value.…”

Section: Introductionmentioning

confidence: 99%

Indoloquinolizidine Derivatives as Novel and Potent Apoptosis Inducers and Cell‐Cycle Blockers

Wehner¹,

Nören‐Müller²,

Müller³

et al. 2008

ChemBioChem

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A collection of approximately 11 000 natural-product derived and inspired compounds was screened for potential apoptosis inducers in the human tumour cell lines HepG2 (liver), HeLa (cervix) and MCF-7 (breast) by means of MTT and ATP-luminescence assays, automated cell counting, caspase 3/7 assay as well as by fluorescence activated cell sorting (FACS) analysis. A group of seven indoloquinolizidine derivatives was identified that exhibited IC(50) values for cell proliferation as low as 2 mumol L(-1), with no major necrosis of cells detectable. At the same time, an increase in the rate of apoptosis of up to 600 % relative to the reference level was observed. FACS analysis indicated that these effects are related to an arrest of cells in the G(2)M phase of the cell cycle.

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Phloroglucinolderivate Guttiferon G, Aristoforin und Hyperforin: Inhibitoren der menschlichen Sirtuine SIRT1 und SIRT2

Cited by 17 publications

References 36 publications

Neurotrophic Natural Products: Chemistry and Biology

Neurotrophic Natural Products: Chemistry and Biology

Thiobarbiturates as Sirtuin Inhibitors: Virtual Screening, Free‐Energy Calculations, and Biological Testing

Indoloquinolizidine Derivatives as Novel and Potent Apoptosis Inducers and Cell‐Cycle Blockers

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