ABSTRACT
Hurler syndrome, a type of Mucopolysaccharidosis type I, is an inherited disorder caused by the accumulation of glycosaminoglycans (GAG) due to a deficiency in lysosomal α-L-iduronidase (IDUA), resulting in multiorgan dysfunction. In many patients with Hurler syndrome, IDUA proteins are not produced due to nonsense mutations in their genes; therefore, readthrough-inducing compounds, such as gentamycin, are expected to restore IDUA proteins by skipping the premature termination codon. In the present study, we synthesized a series of chromenopyridine derivatives to identify novel readthrough-inducing compounds. The readthrough-inducing activities of synthesized compounds were examined by measuring cellular IDUA activities and GAG concentrations in Hurler syndrome patient-derived cells. Compounds with a difluorophenyl group at the 2-position of chromenopyridine, a cyclobutyl group at the 3-position, and a basic side chain or basic fused ring exhibited excellent readthrough-inducing activities. KY-640, a chromenopyridine derivative with a tetrahydroisoquinoline sub-structure, increased the cellular IDUA activities of patient-derived cells by 3.2-fold at 0.3 µM and significantly reduced GAG concentrations, and also significantly increased enzyme activity in mouse models, suggesting its therapeutic potential in patients with Hurler syndrome.
Subject(s)
Mucopolysaccharidosis I , Mice , Animals , Humans , Mucopolysaccharidosis I/drug therapy , Mucopolysaccharidosis I/genetics , Codon, NonsenseABSTRACT
The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.
Subject(s)
Mucopolysaccharidosis I , Animals , Rats , Mucopolysaccharidosis I/drug therapy , Mucopolysaccharidosis I/genetics , Codon, Nonsense , Administration, Oral , Biological Assay , TriazolesABSTRACT
Siloxy-N-silylketenimines generated in situ from O-silyl cyanohydrins were converted to α-ketoamides by brief exposure to air or oxygen. Oxidation under extremely mild conditions can be explained by assuming the intermediacy of a 3-imino-1,2-dioxetane derivative generated via triplet-singlet intersystem crossing after the reaction of siloxy-N-silylketenimines with triplet oxygen.
ABSTRACT
Reactions of γ-bromo-α,ß,γ,δ-unsaturated acylsilanes with KCN under phase-transfer catalyst conditions using n-Bu4NBr afforded 2-cyano-2-siloxyvinylallenes via a tandem process that involves a nucleophilic attack of a cyanide ion and a Brook rearrangement induced conjugate vinylic 1,4-elimination. Use of a chiral cyanide ion source, derived from KCN and quaternary ammonium bromide derived from cinchona alkaloids, provided nonracemic allene derivatives. Based on this result and the reaction using a chiral hydride ion source, we propose a reaction pathway in which a Brook rearrangement mediated vinylic conjugate 1,4-elimination occurs in a syn alignment between the C-Br bond and C-Si bond in the silicate intermediate.
ABSTRACT
The development of a new class of hydrazide type organocatalyst, (4R,5R)-1,3-bis(isopropylamino)-4,5-dihenylimidazolidin-2-one 2a, for enantioselective Diels-Alder reactions between cyclopentadiene and α,ß-unsaturated aldehydes are presented. The new organocatalyst 2a promoted the reaction, affording Diels-Alder adducts in good yields with good levels of enantioselectivity.