Syntheses and bioactivities of tricyclic pyrones

Abstract

In search of compounds that ameliorate the toxicity of amyloid-β (Aβ) peptides, new derivatives of tricyclic pyrones ( 1– 7 ) were synthesized and their biological activities evaluated. The carboxylic ester and amide derivatives 1– 4 were synthesized from a selective carboxylation of C3 methyl of (5a S,7 S)-{7-Isopropenyl-3-methyl-1 H,7 H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3- b][1]benzopyran ( 8 ) with LDA followed by benzyl chloroformate or carbon dioxide to provide ester 1 and carboxylic acid 9 , respectively. Three isomeric tricyclic pyrone, 5– 7 , containing adenine moiety at C7 side chain were synthesized from the alkylation of mesylate 13 with adenine, and displacement of chloropurine 15 with amine 14 . Although C3-benzyloxycarbonylmethyl analogs 1– 3 have marginal ACAT and CETP activities, their modified aspartate analog 4 and C3-methyl-C7-( N3-adeninyl)-2-propyl analog 6 show a significant effect in protecting against neuron-cell death from the toxicity of intracellular accumulation of Aβ or Aβ-containing C-terminal fragments (CTF) of amyloid β precursor protein (APP). N9-Adenine analog 5 is 20-fold less effective than N3-adenine derivative 6 in the protection of neuron-cell death induced by Aβ, while N10-adenine analog 7 was inactive. As a result of this study, compounds 4 and 6 will well serve as lead compounds for further studies of the mechanism of action of Aβ-and CTF-induced neuron-cell death, studies which should enhance the future development of new drugs for the prevention and treatment of AD.