In search of compounds that ameliorate the toxicity of amyloid-b (Ab) 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 (5aS,7S)-{7-Isopropenyl-3-methyl-1H, 7H-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 Ab or Ab-containing C-terminal fragments (CTF) of amyloid b 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 Ab, 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 Ab-and CTF-induced neuron-cell death, studies which should enhance the future development of new drugs for the prevention and treatment of AD.