Lucas SD

References (6)

Title : Chemoproteomics-Enabled Identification of 4-Oxo-beta-Lactams as Inhibitors of Dipeptidyl Peptidases 8 and 9 - Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
Author(s) : Carvalho LAR , Ross B , Fehr L , Bolgi O , Wohrle S , Lum KM , Podlesainski D , Vieira AC , Kiefersauer R , Felix R , Rodrigues T , Lucas SD , Gross O , Geiss-Friedlander R , Cravatt BF , Huber R , Kaiser M , Moreira R
Ref : Angew Chem Int Ed Engl , : , 2022
Abstract : Dipeptidyl peptidases 8 and 9 (DPP8/9) have gathered interest as drug targets due to their important roles in biological processes like immunity and tumorigenesis. Elucidation of their distinct individual functions remains an ongoing task and could benefit from the availability of novel, chemically diverse and selective chemical tools. Here, we report the activity-based protein profiling (ABPP)-mediated discovery of 4-oxo-beta-lactams as potent, non-substrate-like nanomolar DPP8/9 inhibitors. X-ray crystallographic structures revealed different ligand binding modes for DPP8 and DPP9, including an unprecedented targeting of an extended S2' (eS2') subsite in DPP8. Biological assays confirmed inhibition at both target and cellular levels. Altogether, our integrated chemical proteomics and structure-guided small molecule design approach led to novel DPP8/9 inhibitors with alternative molecular inhibition mechanisms, delivering the highest selectivity index reported to date.
ESTHER : Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
PubMedSearch : Carvalho_2022_Angew.Chem.Int.Ed.Engl_61_e202210498
PubMedID: 36089535
Gene_locus related to this paper: human-DPP8 , human-DPP9

Title : Synthesis, Biological Evaluation, and Docking Studies of Open-chain Carbohydrate Amides as Acetylcholinesterase Inhibitors - Goncalves-Pereira_2022_Med.Chem__
Author(s) : Goncalves-Pereira R , Figueiredo JA , Lucas SD , Garcia-Moreno MI , Mellet CO , Rauter AP , Ismael MI
Ref : Med Chem , : , 2022
Abstract : INTRODUCTION: Alzheimer's disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors. METHOD: Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4-lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide were performed to assign binding interactions with acetylcholinesterase and determine the key features for bioactivity. RESULT: The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly due to Pi-Pi stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide. CONCLUSION: Bonding is also significant through sugar interaction with the residues Tyr124 and Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant for the observed binding to acetylcholinesterase.
ESTHER : Goncalves-Pereira_2022_Med.Chem__
PubMedSearch : Goncalves-Pereira_2022_Med.Chem__
PubMedID: 36476428

Title : 3-Oxo-beta-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling - Carvalho_2020_ACS.Chem.Biol_15_878
Author(s) : Carvalho LAR , Almeida VT , Brito JA , Lum KM , Oliveira TF , Guedes RC , Goncalves LM , Lucas SD , Cravatt BF , Archer M , Moreira R
Ref : ACS Chemical Biology , 15 :878 , 2020
Abstract : 3-Oxo-beta-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-beta-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-beta-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-beta-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.
ESTHER : Carvalho_2020_ACS.Chem.Biol_15_878
PubMedSearch : Carvalho_2020_ACS.Chem.Biol_15_878
PubMedID: 32176480

Title : Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential - Loesche_2018_Bioorg.Chem_85_23
Author(s) : Loesche A , Kowitsch A , Lucas SD , Al-Halabi Z , Sippl W , Al-Harrasi A , Csuk R
Ref : Bioorg Chem , 85 :23 , 2018
Abstract : Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer's disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman's assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of Ki=4.29muM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing Ki=1.72microM and Ki'=1.28muM, respectively.
ESTHER : Loesche_2018_Bioorg.Chem_85_23
PubMedSearch : Loesche_2018_Bioorg.Chem_85_23
PubMedID: 30599410

Title : Converting maslinic acid into an effective inhibitor of acylcholinesterases - Schwarz_2015_Eur.J.Med.Chem_103_438
Author(s) : Schwarz S , Loesche A , Lucas SD , Sommerwerk S , Serbian I , Siewert B , Pianowski E , Csuk R
Ref : Eur Journal of Medicinal Chemistry , 103 :438 , 2015
Abstract : During the last decade, maslinic acid has been evaluated for many biological properties, e.g. as an anti-tumor or an anti-viral agent but also as a nutraceutical. The potential of maslinic acid and related derivatives to act as inhibitors of acetyl- or butyryl-cholinesterase was examined in this communication in more detail. Cholinesterases do still represent an interesting group of target enzymes with respect to the investigation and treatment of the Alzheimer's disease and other dementia illnesses as well. Although other triterpenoic acids have successfully been tested for their ability to act as inhibitors of cholinesterases, up to now maslinic acid has not been part of such studies. For this reason, three series of maslinic acid derivatives possessing modifications at different centers were synthesized and subjected to Ellman's assay to determine their inhibitory strength and type of inhibitory action. While parent compound maslinic acid was no inhibitor in these assays, some of the compounds exhibited an inhibition of acetylcholinesterase in the single-digit micro-molar range. Two compounds were identified as inhibitors of butyrylcholinesterase showing inhibition constants comparable to those of galantamine, a drug often used in the treatment of Alzheimer's disease. Furthermore, additional selectivity as well as cytotoxicity studies were performed underlining the potential of several derivatives and qualifying them for further investigations. Docking studies revealed that the different kinetic behavior within the same compound series may be explained by the ability of the compounds to enter the active site gorge of AChE.
ESTHER : Schwarz_2015_Eur.J.Med.Chem_103_438
PubMedSearch : Schwarz_2015_Eur.J.Med.Chem_103_438
PubMedID: 26383128

Title : Amino derivatives of glycyrrhetinic acid as potential inhibitors of cholinesterases - Schwarz_2014_Bioorg.Med.Chem_22_3370
Author(s) : Schwarz S , Lucas SD , Sommerwerk S , Csuk R
Ref : Bioorganic & Medicinal Chemistry , 22 :3370 , 2014
Abstract : The development of remedies against the Alzheimer's disease (AD) is one of the biggest challenges in medicinal chemistry nowadays. Although not completely understood, there are several strategies fighting this disease or at least bringing some relief. During the progress of AD, the level of acetylcholine (ACh) decreases; hence, a therapy using inhibitors should be of some benefit to the patients. Drugs presently used for the treatment of AD inhibit the two ACh controlling enzymes, acetylcholinesterase as well as butyrylcholinesterase; hence, the design of selective inhibitors is called for. Glycyrrhetinic acid seems to be an interesting starting point for the development of selective inhibitors. Although its glycon, glycyrrhetinic acid is known for being an AChE activator, several derivatives, altered in position C-3 and C-30, exhibited remarkable inhibition constants in micro-molar range. Furthermore, five representative compounds were subjected to three more enzyme assays (on carbonic anhydrase II, papain and the lipase from Candida antarctica) to gain information about the selectivity of the compounds in comparison to other enzymes. In addition, photometric sulforhodamine B assays using murine embryonic fibroblasts (NiH 3T3) were performed to study the cytotoxicity of these compounds. Two derivatives, bearing either a 1,3-diaminopropyl or a 1H-benzotriazolyl residue, showed a BChE selective inhibition in the single-digit micro-molar range without being cytotoxic up to 30muM. In silico molecular docking studies on the active sites of AChE and BChE were performed to gain a molecular insight into the mode of action of these compounds and to explain the pronounced selectivity for BChE.
ESTHER : Schwarz_2014_Bioorg.Med.Chem_22_3370
PubMedSearch : Schwarz_2014_Bioorg.Med.Chem_22_3370
PubMedID: 24853320