Groselj U

References (6)

Title : Synthesis and Cholinesterase Inhibitory Activity of Selected Indole-Based Compounds - Groselj_2023_Acta.Chim.Slov_70_545
Author(s) : Groselj U , Grsic M , Meden A , Knez D , Jukic M , Svete J , Gobec S
Ref : Acta Chim Slov , 70 :545 , 2023
Abstract : Synthesis and anticholinesterase activity of 18 previously unpublished indole- and tryptophan-derived compounds are disclosed. These sp3-rich compounds containing an indole structural unit exhibit selective submicromolar inhibition of human butyrylcholinesterase (hBChE). The structures of the newly synthesized compounds were confirmed by 1H and 13C NMR, IR spectroscopy, and high-resolution mass spectrometry.
ESTHER : Groselj_2023_Acta.Chim.Slov_70_545
PubMedSearch : Groselj_2023_Acta.Chim.Slov_70_545
PubMedID: 38124635

Title : From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series - Meden_2022_Eur.J.Med.Chem_230_114248
Author(s) : Meden A , Knez D , Brazzolotto X , Nachon F , Dias J , Svete J , Stojan J , Groselj U , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 230 :114248 , 2022
Abstract : Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold) (Chierrito et al., 2018).. Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the neccessary structural infromation for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.
ESTHER : Meden_2022_Eur.J.Med.Chem_230_114248
PubMedSearch : Meden_2022_Eur.J.Med.Chem_230_114248
PubMedID: 35299116
Gene_locus related to this paper: human-BCHE

Title : Early Discovery of Children With Lysosomal Acid Lipase Deficiency With the Universal Familial Hypercholesterolemia Screening Program - Sustar_2022_Front.Genet_13_936121
Author(s) : Sustar U , Groselj U , Trebusak Podkrajsek K , Mlinaric M , Kovac J , Thaler M , Drole Torkar A , Skarlovnik A , Battelino T , Hovnik T
Ref : Front Genet , 13 :936121 , 2022
Abstract : Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive lysosomal storage disorder, caused by homozygous or compound heterozygous pathogenic variants in the LIPA gene. Clinically, LAL-D is under- and misdiagnosed, due to similar clinical and laboratory findings with other cholesterol or liver misfunctions. As a part of the Slovenian universal familial hypercholesterolemia (FH) screening, LAL-D is screened as a secondary condition among other rare dyslipidemias manifesting with hypercholesterolemia. Out of 669 children included, three were positive for a homozygous disease-causing splicing variant NM_000235.4: c.894G > A (NP_000226.2:p. Gln298Gln) in the LIPA gene (NG_008194.1). The mean age by the diagnosis of LAL-D was 9.8 +/- 0.9 years. Moreover, all three LAL-D-positive children had an important elevation of transaminases and decreased activity of the lysosomal acid lipase enzyme. Abdominal MRI in all children detected an enlarged liver but a normal-sized spleen. In conclusion, universal FH screening algorithms with the confirmatory genetic analysis in the pediatric population enable also rare dyslipidemia detection at an early age. An important clinical criterion for differentiation between FH and the LAL-D-positive children has elevated transaminase levels (AST and ALT). In all three LAL-D positive children, an improvement in cholesterol and transaminase levels and steatosis of the liver has been seen after early treatment initiation.
ESTHER : Sustar_2022_Front.Genet_13_936121
PubMedSearch : Sustar_2022_Front.Genet_13_936121
PubMedID: 35903350
Gene_locus related to this paper: human-LIPA

Title : Structure-activity relationship study of tryptophan-based butyrylcholinesterase inhibitors - Meden_2020_Eur.J.Med.Chem_208_112766
Author(s) : Meden A , Knez D , Malikowska-Racia N , Brazzolotto X , Nachon F , Svete J , Salat K , Groselj U , Gobec S
Ref : Eur Journal of Medicinal Chemistry , 208 :112766 , 2020
Abstract : A series of tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors was designed and synthesized. Compounds were optimized in terms of potency, selectivity, and synthetic accessibility. The crystal structure of the inhibitor 18 in complex with BChE revealed the molecular basis for its low nanomolar inhibition (IC50 = 2.8 nM). The favourable in vitro results enabled a first-in-animal in vivo efficacy and safety trial, which demonstrated a positive impact on fear-motivated and spatial long-term memory retrieval without any concomitant adverse motor effects. Altogether, this research culminated in a handful of new lead compounds with promising potential for symptomatic treatment of patients with Alzheimers disease.
ESTHER : Meden_2020_Eur.J.Med.Chem_208_112766
PubMedSearch : Meden_2020_Eur.J.Med.Chem_208_112766
PubMedID: 32919297
Gene_locus related to this paper: human-BCHE

Title : Tryptophan-derived butyrylcholinesterase inhibitors as promising leads against Alzheimer's disease - Meden_2019_Chem.Commun.(Camb)_55_3765
Author(s) : Meden A , Knez D , Jukic M , Brazzolotto X , Grsic M , Pislar A , Zahirovic A , Kos J , Nachon F , Svete J , Gobec S , Groselj U
Ref : Chem Commun (Camb) , 55 :3765 , 2019
Abstract : We have identified tryptophan-based selective nanomolar butyrylcholinesterase (BChE) inhibitors. They are defined according to their chemical modularity, novel binding mode revealed by five solved crystal structures with human BChE, low cytotoxicity, and predicted permeability of the blood-brain barrier. Altogether, these factors indicate their potential as unique lead compounds for symptomatic therapy against Alzheimer's disease.
ESTHER : Meden_2019_Chem.Commun.(Camb)_55_3765
PubMedSearch : Meden_2019_Chem.Commun.(Camb)_55_3765
PubMedID: 30864579
Gene_locus related to this paper: human-BCHE

Title : Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides - Groselj_2016_Mol.Divers_20_667
Author(s) : Groselj U , Golobic A , Knez D , Hrast M , Gobec S , Ricko S , Svete J
Ref : Mol Divers , 20 :667 , 2016
Abstract : The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer's disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase [Formula: see text] ([Formula: see text] values [Formula: see text] and [Formula: see text], respectively).
ESTHER : Groselj_2016_Mol.Divers_20_667
PubMedSearch : Groselj_2016_Mol.Divers_20_667
PubMedID: 27017352