ABSTRACT
This paper explores the computer modelling aided design and synthesis of ß-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation in both an enzymatic and cellular setting. We investigated the importance of individual stereocenters, variations in structure-activity relationships along with factors influencing cell penetration. To achieve these goals we modified nitrogen heterocycles in terms of ring size, side chains present and ring nitrogen derivatization. By reducing the inhibitor interactions with the active site down to the essentials we were able to determine that besides the established 2S,3R trans-relationship, the presence and stereochemistry of the CH2OH side chain is of crucial importance for activity. In terms of cellular penetration, N-butyl side chains favour cellar uptake, while hydroxy- and carboxy-group bearing sidechains on the ring nitrogen retarded cellular penetration. Furthermore we show an early proof of principle study that ß-N-acetylhexosaminidase inhibitors can be applicable to use in a potential anti-invasive anti-cancer strategy.
ABSTRACT
The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol. Four, six, nine and twelve carbon atom alkyl chains have been introduced. The study of two distinct D-gluco and L-ido stereochemistries for the tetrol pattern as well as R and S configurations for the C-2 carbon bearing the C-alkyl chain is reported. We observed that C-alkylation of the L-ido tetrahydroxylated azepane converts it from an α-L-fucosidase to a ß-glucosidase and ß-galactosidase inhibitor while N-alkylation of the D-gluco iminosugar significantly improves its inhibition profile leading to potent ß-glucosidase, ß-galactosidase, α-L-rhamnosidase and ß-glucuronidase inhibitors whatever the stereochemistry of the alkyl chain. Interestingly, the N-alkyl chain length usually parallels the azepane inhibitor potency as exemplified by the identification of a potent glucocerebrosidase inhibitor (Ki 1 µM) bearing a twelve carbon atom chain. Additionally, several C-alkyl azepanes demonstrated promising F508del-CFTR correction unlike the parent tetrahydroxyazepanes. None of the C-alkyl and N-alkyl azepanes did inhibit ER α-glucosidases I or II.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Glucosylceramidase/antagonists & inhibitors , Imino Sugars/pharmacology , Alkylation , Crystallography, X-Ray , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucosylceramidase/metabolism , Humans , Imino Sugars/chemical synthesis , Imino Sugars/chemistry , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
X-Ray crystallography unequivocally determined the stereochemistry of the thymine base in the title compound, C(14)H(18)N(2)O(7). The absolute stereochemistry was determined from the use of d-ribose as the starting material. There are two independent mol-ecules in the asymmetric unit (Z' = 2) which exist as N-Hâ¯O hydrogen-bonded pairs in the crystal structure.
ABSTRACT
X-ray crystallography unequivocally confirmed the stereochemistry of the 2-C-methyl group in the title mol-ecule, C(10)H(16)O(6), in which the 1,5-lactone ring exists in a boat conformation. The use of d-galactose in the synthesis determined the absolute stereochemistry. The crystal exists as O-Hâ¯O hydrogen-bonded layers in the ab plane, with each mol-ecule acting as a donor and acceptor for two hydrogen bonds.
ABSTRACT
The crystal structure of the title compound, C(12)H(18)N(2)O(8), exists as O-Hâ¯O hydrogen-bonded layers of mol-ecules running parallel to the ab plane. Each mol-ecule is a donor and acceptor for six hydrogen bonds. The absolute stereochemistry was determined by the use of d-glucuronolactone as the starting material.
ABSTRACT
Reaction of 3-O-benzyl-1,2-O-isopropyl-idene-α-xylo-pentodialdo-1,4-furan-ose with N,N-diethyl-2-(dimethyl-sulfuranil-idene)acetamide gave stereoselectively an ep-oxy-amide, which was regioselectively opened by NaN(3) in dimethyl formamide to give the title compound, C(21)H(30)N(4)O(6). X-ray crystallography confirmed the relative stereochemistry of the title compound and the absolute configuration was determined by the use of d-glucose as the starting material. There are two mol-ecules in the asymmetric unit (Z' = 2). The crystal structure consists of two types of chains of O-Hâ¯O hydrogen-bonded mol-ecules running parallel to the b axis, with each mol-ecule acting as a donor and acceptor of one hydrogen bond.