Syntheses and bioactivities of tricyclic pyrones

In search of compounds that ameliorate the toxicity of amyloid-β (Aβ) peptides, new derivatives of tricyclic pyrones () were synthesized and their biological activities evaluated. The carboxylic ester and amide derivatives were synthesized from a selective carboxylation of C3 methyl of (5aS,7S)-{7-Isopropenyl-3-methyl-1H,7H-5a,6,8,9-tetrahydro-1-oxopyrano[4,3-b][1]benzopyran () with LDA followed by benzyl chloroformate or carbon dioxide to provide ester and carboxylic acid , respectively. Three isomeric tricyclic pyrone, , containing adenine moiety at C7 side chain were synthesized from the alkylation of mesylate with adenine, and displacement of chloropurine with amine . Although C3-benzyloxycarbonylmethyl analogs have marginal ACAT and CETP activities, their modified aspartate analog and C3-methyl-C7-(N3-adeninyl)-2-propyl analog 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 is 20-fold less effective than N3-adenine derivative in the protection of neuron-cell death induced by Aβ, while N10-adenine analog was inactive. As a result of this study, compounds and 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.