Brandt W

References (12)

Title : Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase - Loesche_2019_Molecules_24_
Author(s) : Loesche A , Kahnt M , Serbian I , Brandt W , Csuk R
Ref : Molecules , 24 : , 2019
Abstract : A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman's assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3beta)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low Ki of 0.07 +/- 0.01 microM (Ki' = 2.38 +/- 0.48 microM) for the inhibition of BChE.
ESTHER : Loesche_2019_Molecules_24_
PubMedSearch : Loesche_2019_Molecules_24_
PubMedID: 30866589

Title : Novel 12-hydroxydehydroabietylamine derivatives act as potent and selective butyrylcholinesterase inhibitors - Loesche_2019_Bioorg.Chem_90_103092
Author(s) : Loesche A , Wiemann J , Rohmer M , Brandt W , Csuk R
Ref : Bioorg Chem , 90 :103092 , 2019
Abstract : The skeleton of the diterpene dehydroabietylamine was modified, and a set of 12-hydroxy-dehydroabietylamine derivatives was obtained. The compounds were screened in colorimetric Ellman's assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). Additional investigations concerning the enzyme kinetics were performed and showed 12-hydroxy-N-(4-nitro-benzoyl)dehydroabietylamine (13) and 12-hydroxy-N-(isonicotinoyl)dehydroabietylamine (17) as selective BChE inhibitors holding good inhibition constants Ki=0.72+/-0.06muM and Ki=0.86+/-0.19muM, respectively.
ESTHER : Loesche_2019_Bioorg.Chem_90_103092
PubMedSearch : Loesche_2019_Bioorg.Chem_90_103092
PubMedID: 31280014

Title : Piperlongumine B and analogs are promising and selective inhibitors for acetylcholinesterase - Wiemann_2017_Eur.J.Med.Chem_139_222
Author(s) : Wiemann J , Karasch J , Loesche A , Heller L , Brandt W , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 139 :222 , 2017
Abstract : Piperlongumine B (19), an alkaloid previously isolated from long pepper (Piper longum) has been synthesized for the first time in a short sequence and in good yield together with 19 analogs. Screening of these compounds in Ellman's assays showed several of them to be good inhibitors of acetylcholinesterase while being less active for butyrylcholinesterase. Activity of the compounds increased with the ring size of the heterocycle, and a maximum of activity was observed for an analog holding 12 methylene groups in the aliphatic side chain. These compounds may be regarded as promising candidates for the development of efficient inhibitors of acetylcholinesterase being useful for the treatment of Alzheimer's disease.
ESTHER : Wiemann_2017_Eur.J.Med.Chem_139_222
PubMedSearch : Wiemann_2017_Eur.J.Med.Chem_139_222
PubMedID: 28802122

Title : Amino derivatives of platanic acid act as selective and potent inhibitors of butyrylcholinesterase - Heller_2016_Eur.J.Med.Chem_126_652
Author(s) : Heller L , Kahnt M , Loesche A , Grabandt P , Schwarz S , Brandt W , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 126 :652 , 2016
Abstract : A set of thirtyfive 30-norlupan derivatives (2-36) was prepared from the natural triterpenoid platanic acid (PA), and the hydroxyl group at C-3, the carboxyl group at C-17 and the carbonyl group at C-20 were modified. These derivatives were tested for their inhibitory activity for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) using Ellman's assay. Extra enzyme kinetic studies were performed. The most active compound was (3beta, 20R)-3-acetyloxy-20-amino-30-norlupan-28-oate (32) showing a Ki value of 0.01 +/- 0.003 muM for BChE. This compound proved to be a selective (FB = 851), mixed-type inhibitor for BChE.
ESTHER : Heller_2016_Eur.J.Med.Chem_126_652
PubMedSearch : Heller_2016_Eur.J.Med.Chem_126_652
PubMedID: 27936444

Title : Repurposing N,N'-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases - Loesche_2016_Eur.J.Med.Chem_125_430
Author(s) : Loesche A , Wiese J , Sommerwerk S , Simon V , Brandt W , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 125 :430 , 2016
Abstract : Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.
ESTHER : Loesche_2016_Eur.J.Med.Chem_125_430
PubMedSearch : Loesche_2016_Eur.J.Med.Chem_125_430
PubMedID: 27689726

Title : Cation-Pi and Pi-Pi stacking interactions allow selective inhibition of butyrylcholinesterase by modified quinine and cinchonidine alkaloids - Nawaz_2011_Biochem.Biophys.Res.Commun_404_935
Author(s) : Nawaz SA , Ayaz M , Brandt W , Wessjohann LA , Westermann B
Ref : Biochemical & Biophysical Research Communications , 404 :935 , 2011
Abstract : Scaffold varied quaternized quinine and cinchonidine alkaloid derivatives were evaluated for their selective butyrylcholinesterase (BChE) inhibitory potential. K(i) values were between 0.4-260.5microM (non-competitive inhibition) while corresponding K(i)values to acetylcholinesterase (AChE) ranged from 7.0-400microM exhibiting a 250-fold selectivity for BChE. Docking arrangements (GOLD, PLANT) revealed that the extended aromatic moieties and the quaternized nitrogen of the inhibitors were responsible for specific Pi-Pi stacking and Pi-cation interactions with the choline binding site and the peripheral anionic site of BChE's active site.
ESTHER : Nawaz_2011_Biochem.Biophys.Res.Commun_404_935
PubMedSearch : Nawaz_2011_Biochem.Biophys.Res.Commun_404_935
PubMedID: 21185266

Title : Acetylcholinesterase inhibitors from the toadstool Cortinarius infractus - Geissler_2010_Bioorg.Med.Chem_18_2173
Author(s) : Geissler T , Brandt W , Porzel A , Schlenzig D , Kehlen A , Wessjohann L , Arnold N
Ref : Bioorganic & Medicinal Chemistry , 18 :2173 , 2010
Abstract : Inhibition of acetylcholinesterase (AChE) and therefore prevention of acetylcholine degradation is one of the most accepted therapy opportunities for Alzheimer s disease (AD), today. Due to lack of selectivity of AChE inhibitor drugs on the market, AD-patients suffer from side effects like nausea or vomiting. In the present study the isolation of two alkaloids, infractopicrin (1) and 10-hydroxy-infractopicrin (2), from Cortinarius infractus Berk. (Cortinariaceae) is presented. Both compounds show AChE-inhibiting activity and possess a higher selectivity than galanthamine. Docking studies show that lacking pi-pi-interactions in butyrylcholinesterase (BChE) are responsible for selectivity. Studies on other AD pathology related targets show an inhibitory effect of both compounds on self-aggregation of Abeta-peptides but not on AChE induced Abeta-peptide aggregation. Low cytotoxicity as well as calculated pharmacokinetic data suggest that the natural products could be useful candidates for further drug development.
ESTHER : Geissler_2010_Bioorg.Med.Chem_18_2173
PubMedSearch : Geissler_2010_Bioorg.Med.Chem_18_2173
PubMedID: 20176490

Title : Non-substrate peptides influencing dipeptidyl peptidase IV\/CD26 activity and immune cell function - Wrenger_2008_Front.Biosci_13_3194
Author(s) : Wrenger S , Faust J , Mrestani-Klaus C , Brandt W , Thielitz A , Neubert K , Reinhold D
Ref : Front Biosci , 13 :3194 , 2008
Abstract : Investigations using inhibitors of dipeptidyl peptidase IV (DP IV) activities and DP IV-/- mice indicated an immunoregulatory role of DP IV that could not be compensated by DP IV-like enzymes. The HIV-1 Tat protein was identified as the first natural inhibitor of DP IV and as immunosuppressor. This review summarizes our investigations on the identification of the amino acid motif of Tat responsible for DP IV inhibition and of endogenous DP IV-inhibitory ligands that suppress immune cell activation. Examinations on numerous peptides carrying the N-terminal Xaa-Xaa-Pro motif of Tat revealed that tryptophan at position two strongly enhanced DP IV inhibition and immunosuppression. Here, we present evidence that the thromboxane A2 receptor exposing N-terminal Met-Trp-Pro at the cell surface could be a potential endogenous, inhibitory DP IV ligand. Moreover, our data suggest that the major envelope proteins p37k of the orthopoxviruses variola virus and vaccinia virus, as well as the B2L antigen of the parapoxvirus orf, that also carry N-terminal Met-Trp-Pro, could mediate immunosuppressive effects. Further examinations are in progress to identify new physiologic, inhibitory DP IV ligands and to enlighten the mechanism underlying the DP IV-mediated effects.
ESTHER : Wrenger_2008_Front.Biosci_13_3194
PubMedSearch : Wrenger_2008_Front.Biosci_13_3194
PubMedID: 18508427

Title : Structure determinants and substrate recognition of serine carboxypeptidase-like acyltransferases from plant secondary metabolism - Stehle_2006_FEBS.Lett_580_6366
Author(s) : Stehle F , Brandt W , Milkowski C , Strack D
Ref : FEBS Letters , 580 :6366 , 2006
Abstract : Structures of the serine carboxypeptidase-like enzymes 1-O-sinapoyl-beta-glucose:L-malate sinapoyltransferase (SMT) and 1-O-sinapoyl-beta-glucose:choline sinapoyltransferase (SCT) were modeled to gain insight into determinants of specificity and substrate recognition. The structures reveal the alpha/beta-hydrolase fold as scaffold for the catalytic triad Ser-His-Asp. The recombinant mutants of SMT Ser173Ala and His411Ala were inactive, whereas Asp358Ala displayed residual activity of 20%. 1-O-sinapoyl-beta-glucose recognition is mediated by a network of hydrogen bonds. The glucose moiety is recognized by a hydrogen bond network including Trp71, Asn73, Glu87 and Asp172. The conserved Asp172 at the sequence position preceding the catalytic serine meets sterical requirements for the glucose moiety. The mutant Asn73Ala with a residual activity of 13% underscores the importance of the intact hydrogen bond network. Arg322 is of key importance by hydrogen bonding of 1-O-sinapoyl-beta-glucose and L-malate. By conformational change, Arg322 transfers L-malate to a position favoring its activation by His411. Accordingly, the mutant Arg322Glu showed 1% residual activity. Glu215 and Arg219 establish hydrogen bonds with the sinapoyl moiety. The backbone amide hydrogens of Gly75 and Tyr174 were shown to form the oxyanion hole, stabilizing the transition state. SCT reveals also the catalytic triad and a hydrogen bond network for 1-O-sinapoyl-beta-glucose recognition, but Glu274, Glu447, Thr445 and Cys281 are crucial for positioning of choline.
ESTHER : Stehle_2006_FEBS.Lett_580_6366
PubMedSearch : Stehle_2006_FEBS.Lett_580_6366
PubMedID: 17094968
Gene_locus related to this paper: arath-SCP19 , arath-SCP8

Title : Development of a tertiary-structure model of the C-terminal domain of DPP IV - Brandt_2000_Adv.Exp.Med.Biol_477_97
Author(s) : Brandt W
Ref : Advances in Experimental Medicine & Biology , 477 :97 , 2000
Abstract : Based on the recently published structure of prolyl oligopeptidase (POP) a model of the C-terminal part of dipeptidyl peptidase IV (DPP IV) which contains the active site has been developed. The structure of the model of DPP IV shows considerable similarity to the structure of POP particularly in the active site. A hydrophobic pocket (Tyr666, Tyr670, Tyr 631, Val556) forms the S1-binding site for recognition of proline. Tyr547 may stabilise the oxyanion formed in the tetrahedral intermediates by a strong hydrogen bond. The positively charged N-terminus of ligands of DPP IV is recognised by forming a salt bridge with the acidic side chain Glu668. A second hydrophobic pocket (S2' to S5') may represent an important binding site for HIV-1 Tat-protein derivatives, chemokines and others.
ESTHER : Brandt_2000_Adv.Exp.Med.Biol_477_97
PubMedSearch : Brandt_2000_Adv.Exp.Med.Biol_477_97
PubMedID: 10849734

Title : A molecular model of the active site of dipeptidyl peptidase IV. Explanation of the substrate specificity and interaction with inhibitors -
Author(s) : Brandt W
Ref : Advances in Experimental Medicine & Biology , 421 :171 , 1997
PubMedID: 9330694

Title : A model of the active site of dipeptidyl peptidase IV predicted by comparative molecular field analysis and molecular modelling simulations - Brandt_1995_Int.J.Pept.Protein.Res_46_494
Author(s) : Brandt W , Lehmann T , Thondorf I , Born I , Schutkowski M , Rahfeld JU , Neubert K , Barth A
Ref : Int J Pept Protein Res , 46 :494 , 1995
Abstract : A molecular model of the active site of the serine protease dipeptidyl peptidase IV (DPP IV or CD26) has been developed on the basis of comparative molecular field analysis (CoMFA) of competitive inhibitors and by force field calculations. By application of CoMFA experimentally obtained inhibition constants Ki have been successfully predicted. The resulting steric and electrostatic coefficients of CoMFA were used for the development of the molecular model. The main assumptions of the model are the recognition of substrates or inhibitors by the side chains of a tyrosine (S1-position) and a tryptophan residue (S2-position). The model helps us to understand a multitude of experimental data regarding the substrate specificity of this enzyme as well as results obtained by genetic engineering experiments by other authors. General conclusions concerning a new family of serine proteases are drawn and discussed.
ESTHER : Brandt_1995_Int.J.Pept.Protein.Res_46_494
PubMedSearch : Brandt_1995_Int.J.Pept.Protein.Res_46_494
PubMedID: 8748710