Winckler T

References (8)

Title : Evaluation of gamma-carboline-phenothiazine conjugates as simultaneous NMDA receptor blockers and cholinesterase inhibitors - Schwarthoff_2021_Bioorg.Med.Chem_46_116355
Author(s) : Schwarthoff S , Tischer N , Sager H , Schatz B , Rohrbach MM , Raztsou I , Robaa D , Gaube F , Arndt HD , Winckler T
Ref : Bioorganic & Medicinal Chemistry , 46 :116355 , 2021
Abstract : Alzheimer's disease (AD) is the most common form of dementia. It is associated with the impairment of memory and other cognitive functions that are mainly caused by progressive defects in cholinergic and glutamatergic signaling in the central nervous system. Inhibitors of acetylcholinesterase (AChE) and ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA) receptor family are currently approved as AD therapeutics. We previously showed using a cell-based assay of NMDA receptor-mediated glutamate-induced excitotoxicity that bis-gamma-carbolinium conjugates are useful NMDA receptor blockers. However, these compounds also act as subnanomolar AChE inhibitors, which may cause serious anticholinergic side effects when applied in vivo. Here, we evaluated new structures containing gamma-carbolines linked to phenothiazine via a propionyl spacer. These compounds were superior to the previously characterized bis-gamma-carbolinium conjugates because they blocked NMDA receptors without requiring a quaternary pyridine N-atom and inhibited AChE with moderate IC(50) values of 0.54-5.3 microM. In addition, these new compounds displayed considerable selectivity for the inhibition of butyrylcholinesterase (BChE; IC(50) = 0.008-0.041 microM), which may be favorable for AD treatment. Inhibitory activities towards the NMDA receptors and AChE were in the same micromolar range, which may be beneficial for equal dosing against multiple targets in AD patients.
ESTHER : Schwarthoff_2021_Bioorg.Med.Chem_46_116355
PubMedSearch : Schwarthoff_2021_Bioorg.Med.Chem_46_116355
PubMedID: 34391122

Title : Multiple Roots of Fruiting Body Formation in Amoebozoa - Hillmann_2018_Genome.Biol.Evol_10_591
Author(s) : Hillmann F , Forbes G , Novohradska S , Ferling I , Riege K , Groth M , Westermann M , Marz M , Spaller T , Winckler T , Schaap P , Glockner G
Ref : Genome Biol Evol , 10 :591 , 2018
Abstract : Establishment of multicellularity represents a major transition in eukaryote evolution. A subgroup of Amoebozoa, the dictyosteliids, has evolved a relatively simple aggregative multicellular stage resulting in a fruiting body supported by a stalk. Protosteloid amoeba, which are scattered throughout the amoebozoan tree, differ by producing only one or few single stalked spores. Thus, one obvious difference in the developmental cycle of protosteliids and dictyosteliids seems to be the establishment of multicellularity. To separate spore development from multicellular interactions, we compared the genome and transcriptome of a Protostelium species (Protostelium aurantium var. fungivorum) with those of social and solitary members of the Amoebozoa. During fruiting body formation nearly 4,000 genes, corresponding to specific pathways required for differentiation processes, are upregulated. A comparison with genes involved in the development of dictyosteliids revealed conservation of >500 genes, but most of them are also present in Acanthamoeba castellanii for which fruiting bodies have not been documented. Moreover, expression regulation of those genes differs between P. aurantium and Dictyostelium discoideum. Within Amoebozoa differentiation to fruiting bodies is common, but our current genome analysis suggests that protosteliids and dictyosteliids used different routes to achieve this. Most remarkable is both the large repertoire and diversity between species in genes that mediate environmental sensing and signal processing. This likely reflects an immense adaptability of the single cell stage to varying environmental conditions. We surmise that this signaling repertoire provided sufficient building blocks to accommodate the relatively simple demands for cell-cell communication in the early multicellular forms.
ESTHER : Hillmann_2018_Genome.Biol.Evol_10_591
PubMedSearch : Hillmann_2018_Genome.Biol.Evol_10_591
PubMedID: 29378020
Gene_locus related to this paper: 9myce-a0a2p6mnh7 , 9myce-a0a2p6myi8 , 9myce-a0a2p6n3r6 , 9myce-a0a2p6n5x6 , 9myce-a0a2p6n6f1 , 9myce-a0a2p6n6w0 , 9myce-a0a2p6nhs0 , 9myce-a0a2p6nvj6 , 9myce-a0a2p6nvr1 , 9myce-a0a2p6p090 , 9myce-a0a2p6p0e3

Title : Virulence determinants of the human pathogenic fungus Aspergillus fumigatus protect against soil amoeba predation - Hillmann_2015_Environ.Microbiol_17_2858
Author(s) : Hillmann F , Novohradska S , Mattern DJ , Forberger T , Heinekamp T , Westermann M , Winckler T , Brakhage AA
Ref : Environ Microbiol , 17 :2858 , 2015
Abstract : Filamentous fungi represent classical examples for environmentally acquired human pathogens whose major virulence mechanisms are likely to have emerged long before the appearance of innate immune systems. In natural habitats, amoeba predation could impose a major selection pressure towards the acquisition of virulence attributes. To test this hypothesis, we exploited the amoeba Dictyostelium discoideum to study its interaction with Aspergillus fumigatus, two abundant soil inhabitants for which we found co-occurrence in various sites. Fungal conidia were efficiently taken up by D. discoideum, but ingestion was higher when conidia were devoid of the green fungal spore pigment dihydroxynaphtalene melanin, in line with earlier results obtained for immune cells. Conidia were able to survive phagocytic processing, and intracellular germination was initiated only after several hours of co-incubation which eventually led to a lethal disruption of the host cell. Besides phagocytic interactions, both amoeba and fungus secreted cross inhibitory factors which suppressed fungal growth or induced amoeba aggregation with subsequent cell lysis, respectively. On the fungal side, we identified gliotoxin as the major fungal factor killing Dictyostelium, supporting the idea that major virulence attributes, such as escape from phagocytosis and the secretion of mycotoxins are beneficial to escape from environmental predators.
ESTHER : Hillmann_2015_Environ.Microbiol_17_2858
PubMedSearch : Hillmann_2015_Environ.Microbiol_17_2858
PubMedID: 25684622
Gene_locus related to this paper: aspfu-AYG1

Title : Evaluation of Homobivalent Carbolines as Designed Multiple Ligands for the Treatment of Neurodegenerative Disorders - Otto_2015_J.Med.Chem_58_6710
Author(s) : Otto R , Penzis R , Gaube F , Adolph O , Fohr KJ , Warncke P , Robaa D , Appenroth D , Fleck C , Enzensperger C , Lehmann J , Winckler T
Ref : Journal of Medicinal Chemistry , 58 :6710 , 2015
Abstract : Neurodegenerative diseases represent a challenge for biomedical research due to their high prevalence and lack of mechanism-based treatments. Because of the complex pathology of neurodegenerative disorders, multifunctional drugs have been increasingly recognized as potential treatments. We identified homobivalent gamma-carbolinium salts as potent inihitors of both cholinesterases, N-methyl-d-aspartate receptors, and monoamine oxidases. Homobivalent gamma-carbolines displayed similar structure-activity relationships on all tested targets and may present promising designed multiple ligands for the treatment of neurodegenerative disorders.
ESTHER : Otto_2015_J.Med.Chem_58_6710
PubMedSearch : Otto_2015_J.Med.Chem_58_6710
PubMedID: 26278660

Title : Beta and gamma carboline derivatives as potential anti-Alzheimer agents: A comparison - Otto_2014_Eur.J.Med.Chem_87C_63
Author(s) : Otto R , Penzis R , Gaube F , Winckler T , Appenroth D , Fleck C , Trankle C , Lehmann J , Enzensperger C
Ref : Eur Journal of Medicinal Chemistry , 87C :63 , 2014
Abstract : Nine novel beta- and gamma-carboline derivatives bearing either methyl-, propargyl- or phenethyl-residues at the indole nitrogen were synthesized and tested as potential anti-Alzheimer drugs. Antagonism of recombinantly expressed NMDA receptors, inhibition of cholinesterases, and radical scavenging properties were determined for all compounds. Some were additionally tested in vivo for their ability to reverse scopolamine-induced cognitive impairment in an 8-arm radial maze experiment with rats. For the most promising candidates, the interaction with muscarinic M1 receptors was also investigated. With this set of compounds assays the influence of the scaffold itself and the substituents can be investigated separately. 5-Methyl-gamma-carboline (6) was the most potent (0.25 mumol/100 g b.w.) compound in the in vivo test and might be a good starting point for the development of novel anti-Alzheimer drugs.
ESTHER : Otto_2014_Eur.J.Med.Chem_87C_63
PubMedSearch : Otto_2014_Eur.J.Med.Chem_87C_63
PubMedID: 25240096

Title : Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents - Rook_2010_J.Med.Chem_53_3611
Author(s) : Rook Y , Schmidtke KU , Gaube F , Schepmann D , Wunsch B , Heilmann J , Lehmann J , Winckler T
Ref : Journal of Medicinal Chemistry , 53 :3611 , 2010
Abstract : Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes that requires multitargeted treatment. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) improve cholinergic signaling in the central nervous system and thus AChE inhibitors are well established in the therapy of AD to improve memory disturbances and other cognitive symptoms. On the other hand, AD patients benefit from reduction of pathologic glutamate-induced, Ca(2+)-mediated excitotoxicity by the N-methyl-d-aspartate receptor (NR) antagonist memantine. New drugs that simultaneously affect both cholinergic transmission and glutamate-induced excitotoxicity may further improve AD treatment. While connecting beta-carboline units by alkylene spacers in two different series of compounds and subsequent evaluation of their AChE/BChE-inhibitory potential, we found that several of these bivalent beta-carbolines were potent NR blockers. The most promising compound was a N(9)-homobivalent beta-carboline with a nonylene spacer, which displayed IC(50) values of 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 microM for NR, respectively.
ESTHER : Rook_2010_J.Med.Chem_53_3611
PubMedSearch : Rook_2010_J.Med.Chem_53_3611
PubMedID: 20361801

Title : [Final IQWiG to Ginkgo biloba] -
Author(s) : Winckler T
Ref : Pharm Unserer Zeit , 38 :454 , 2009
PubMedID: 19711323

Title : The genome of the social amoeba Dictyostelium discoideum - Eichinger_2005_Nature_435_43
Author(s) : Eichinger L , Pachebat JA , Glockner G , Rajandream MA , Sucgang R , Berriman M , Song J , Olsen R , Szafranski K , Xu Q , Tunggal B , Kummerfeld S , Madera M , Konfortov BA , Rivero F , Bankier AT , Lehmann R , Hamlin N , Davies R , Gaudet P , Fey P , Pilcher K , Chen G , Saunders D , Sodergren E , Davis P , Kerhornou A , Nie X , Hall N , Anjard C , Hemphill L , Bason N , Farbrother P , Desany B , Just E , Morio T , Rost R , Churcher C , Cooper J , Haydock S , van Driessche N , Cronin A , Goodhead I , Muzny D , Mourier T , Pain A , Lu M , Harper D , Lindsay R , Hauser H , James K , Quiles M , Madan Babu M , Saito T , Buchrieser C , Wardroper A , Felder M , Thangavelu M , Johnson D , Knights A , Loulseged H , Mungall K , Oliver K , Price C , Quail MA , Urushihara H , Hernandez J , Rabbinowitsch E , Steffen D , Sanders M , Ma J , Kohara Y , Sharp S , Simmonds M , Spiegler S , Tivey A , Sugano S , White B , Walker D , Woodward J , Winckler T , Tanaka Y , Shaulsky G , Schleicher M , Weinstock G , Rosenthal A , Cox EC , Chisholm RL , Gibbs R , Loomis WF , Platzer M , Kay RR , Williams J , Dear PH , Noegel AA , Barrell B , Kuspa A
Ref : Nature , 435 :43 , 2005
Abstract : The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.
ESTHER : Eichinger_2005_Nature_435_43
PubMedSearch : Eichinger_2005_Nature_435_43
PubMedID: 15875012
Gene_locus related to this paper: dicdi-abhd , dicdi-ACHE , dicdi-apra , dicdi-cinbp , dicdi-CMBL , dicdi-crysp , dicdi-DPOA , dicdi-P90528 , dicdi-ppme1 , dicdi-Q8MYE7 , dicdi-q54cf7 , dicdi-q54cl7 , dicdi-q54cm0 , dicdi-q54ct5 , dicdi-q54cu1 , dicdi-q54d54 , dicdi-q54d66 , dicdi-q54dj5 , dicdi-q54dy7 , dicdi-q54ek1 , dicdi-q54eq6 , dicdi-q54et1 , dicdi-q54et7 , dicdi-q54f01 , dicdi-q54g24 , dicdi-q54g47 , dicdi-q54gi7 , dicdi-q54gw5 , dicdi-q54gx3 , dicdi-q54h23 , dicdi-q54h73 , dicdi-q54i38 , dicdi-q54ie5 , dicdi-q54in4 , dicdi-q54kz1 , dicdi-q54l36 , dicdi-q54li1 , dicdi-q54m29 , dicdi-q54n21 , dicdi-q54n35 , dicdi-q54n85 , dicdi-q54qe7 , dicdi-q54qi3 , dicdi-q54qk2 , dicdi-q54rl3 , dicdi-q54rl8 , dicdi-q54sy6 , dicdi-q54sz3 , dicdi-q54t49 , dicdi-q54t91 , dicdi-q54th2 , dicdi-q54u01 , dicdi-q54vc2 , dicdi-q54vw1 , dicdi-q54xe3 , dicdi-q54xl3 , dicdi-q54xu1 , dicdi-q54xu2 , dicdi-q54y48 , dicdi-q54yd0 , dicdi-q54ye0 , dicdi-q54yl1 , dicdi-q54yr8 , dicdi-q54z90 , dicdi-q55bx3 , dicdi-q55d01 , dicdi-q55d81 , dicdi-q55du6 , dicdi-q55eu1 , dicdi-q55eu8 , dicdi-q55fk4 , dicdi-q55gk7 , dicdi-Q54ZA6 , dicdi-q86h82 , dicdi-Q86HC9 , dicdi-Q86HM5 , dicdi-Q86HM6 , dicdi-q86iz7 , dicdi-q86jb6 , dicdi-Q86KU7 , dicdi-q550s3 , dicdi-q552c0 , dicdi-q553t5 , dicdi-q555e5 , dicdi-q555h0 , dicdi-q555h1 , dicdi-q557k5 , dicdi-q558u2 , dicdi-Q869Q8 , dicdi-u554 , dicdi-y9086 , dicdi-q54r44 , dicdi-f172a