ABSTRACT
We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI50 = 5.6 ± 1.1 µM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity.
Subject(s)
Antineoplastic Agents , Butyrylcholinesterase , Cell Proliferation , Cholinesterase Inhibitors , Coumarins , Coumarins/chemistry , Coumarins/pharmacology , Coumarins/chemical synthesis , Butyrylcholinesterase/metabolism , Humans , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cell Proliferation/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Animals , Cell Line, Tumor , Structure-Activity Relationship , Molecular Structure , Drug Screening Assays, Antitumor , Aza Compounds/chemistry , Aza Compounds/pharmacology , Aza Compounds/chemical synthesis , Dose-Response Relationship, Drug , Neurons/drug effectsABSTRACT
The copper-catalysed azide-alkyne cycloaddition was applied to prepare three enantiomeric pairs of heterodimers containing a tacrine residue and a 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) or 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) moiety held together via linkers of variable lengths containing a 1,2,3-triazole ring and 3, 4, or 7 CH2 groups. The heterodimers were tested as inhibitors of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE). The enantiomeric heterodimers with the longest linkers exhibited the highest inhibition potencies for AChE (IC50 = 9.7 nM and 11 nM) and BuChE (IC50 = 8.1 nM and 9.1 nM). AChE exhibited the highest enantioselectivity (ca. 4-fold). The enantiomeric pairs of the heterodimers were found to be inactive (GI50 > 100 µM), or to have weak antiproliferative properties (GI50 = 84-97 µM) against a panel of human cancer cells.
Subject(s)
Acetylcholinesterase , Butyrylcholinesterase , Humans , Tacrine/pharmacology , AlkynesABSTRACT
The synthesis of four heterodimers in which the copper(I)-catalysed azide-alkyne cycloaddition was employed to connect a 1-deoxynojirimycin moiety with a benzotriazole scaffold is reported. The heterodimers were investigated as inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The heterodimers displayed preferential inhibition (> 9) of BuChE over AChE in the micromolar concentration range (IC50 = 7-50 µM). For the most potent inhibitor of BuChE, Cornish-Bowden plots were used, which demonstrated that it behaves as a mixed inhibitor. Modelling studies of the same inhibitor demonstrated that the benzotriazole and 1-deoxynojirimycin moiety is accommodated in the peripheral anionic site and catalytic anionic site, respectively, of AChE. The binding mode to BuChE was different as the benzotriazole moiety is accommodated in the catalytic anionic site.
Subject(s)
Acetylcholinesterase , Butyrylcholinesterase , 1-Deoxynojirimycin , Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , TriazolesABSTRACT
The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Drug Development , Tacrine/pharmacology , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Electrophorus , Molecular Structure , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).
Subject(s)
Indole Alkaloids/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Anti-Infective Agents/pharmacology , Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Indole Alkaloids/metabolism , Plasmodium falciparum/drug effects , Quinolines/metabolism , Structure-Activity RelationshipABSTRACT
We have used the Cu(i)-catalyzed azide-alkyne Huisgen cycloaddition reaction to obtain two families of bivalent heterodimers where tacrine is connected to an azasugar or iminosugar, respectively, via linkers of variable length. The heterodimers were investigated as cholinesterase inhibitors and it was found that their activity increased with the length of the linker. Two of the heterodimers were significantly stronger acetylcholinesterase inhibitors than the monomeric tacrine. Molecular modelling indicated that the longer heterodimers fitted better into the active gorge of acetylcholinesterase than the shorter counterparts and the former provided more efficient simultaneous interaction with the tryptophan residues in the catalytic anionic binding site (CAS) and the peripheral anionic binding site (PAS).
Subject(s)
Cholinesterase Inhibitors/chemistry , Imino Sugars/chemistry , Tacrine/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Animals , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Electrophorus , Enzyme Assays , Horses , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/metabolism , ThermodynamicsABSTRACT
The synthesis of two polyhydroxylated pyrrolidines as 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) analogues bearing a hydrazide moiety is described. The DAB analogues act as selective and potent inhibitors of α-mannosidase in the submicromolar concentration ranges (K i values ranging from 0.23 to 1.4 µM).
ABSTRACT
N 1,N 3-Bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-(N-(oxiran-2-ylmethyl)acetamido)isophthalamide (1), the alleged precursor of several minor byproducts formed when the X-ray contrast agent iodixanol is synthesized from 5-acetamido-N 1,N 3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (2), has been successfully prepared with an overall yield of 25%. Epoxide 1 enabled the confirmation of its presence in the reaction mixture during the preparation of iodixanol when amide 2 was used as the starting material.
ABSTRACT
The preparation of a novel type of iminosugar including a hydrazide imide moiety is described. The sugar hydrazide imides (3S,4S,5R,6R)-1-amino-3,4,5-trihydroxy-6-(hydroxymethyl)-2-iminopiperidine acetate and (3S,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-imino-1-(methylamino)piperidine acetate presented here behave as inhibitors of α/ß-glucosidases in the low micromolar concentration range. The former inhibitor displays a pH-dependent inhibition of ß-glucosidase. The N-methylated counterpart behaves as an anomer-selective competitive micromolar inhibitor of α-glucosidase.
Subject(s)
Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Hydrazines/pharmacology , Imides/pharmacology , Sugars/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glycoside Hydrolases/metabolism , Hydrazines/chemistry , Imides/chemistry , Molecular Conformation , Structure-Activity Relationship , Sugars/chemistryABSTRACT
N-(10-Chloro-9-anthracenemethyl)isofagomine 5 and N-(10-chloro-9-anthracenemethyl)-1-deoxynojirimycin 6 were prepared, and their inhibition of almond ß-glucosidase was measured. The isofagomine derivative 5 was found to be a potent inhibitor, while the 1-deoxynojirimycin derivative 6 displayed no inhibition at the concentrations investigated. Fluorescence spectroscopy of 5 with almond ß-glucosidase at different pH values showed that the inhibitor nitrogen is not protonated when bound to the enzyme. Analysis of pH inhibition data confirmed that 5 binds as the amine to the enzyme's unprotonated dicarboxylate form. This is a radically different binding mode than has been observed with isofagomine and other iminosugars in the literature.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imino Pyranoses/chemistry , beta-Glucosidase/antagonists & inhibitors , Chemistry Techniques, Synthetic , Enzyme Inhibitors/metabolism , Glucosamine/analogs & derivatives , Glucosamine/chemical synthesis , Glucosamine/chemistry , Glucosamine/metabolism , Glucosamine/pharmacology , Hydrogen-Ion Concentration , Imino Pyranoses/chemical synthesis , Imino Pyranoses/metabolism , Imino Pyranoses/pharmacology , Kinetics , Protons , Prunus dulcis/enzymology , Spectrometry, Fluorescence , Structure-Activity Relationship , beta-Glucosidase/metabolismABSTRACT
Substrate selectivity is an important output function for the validation of different enzyme models, catalytic cavity compounds, and reaction mechanisms as demonstrated in this review. In contrast to stereo-, regio-, and chemoselective catalysis, the field of substrate-selective catalysis is under-researched and has to date generated only a few, but important, industrial applications. This review points out the broad spectrum of different reaction types that have been investigated in substrate-selective catalysis. The present review is the first one covering substrate-selective catalysis and deals with reactions in which the substrates involved have the same reacting functionality and the catalysts is used in catalytic or in stoichiometric amounts. The review covers real substrate-selective catalysis, thus only including cases in which substrate-selective catalysis has been observed in competition between substrates.
ABSTRACT
(3R,4R,5R)-2-Imino-3,4-dihydroxy-5-hydroxymethylpiperidine hydrocloride or isofagomidine was synthesized from D-arabinose in 12 steps and an overall yield of 9.9%. The synthesis proceeded by introduction of an aminomethyl group in the 4-position of D-arabinose and conversion of C-1 into a nitrile. The key step in the synthesis was a copper-catalyzed cyclization of aminonitrile to amidine. Isofagomidine was a potent α-mannosidase inhibitor (K(i) = 0.75 µM).