Syntheses and bioactivities of tricyclic pyrones

Duy H. Hua, Xiaodong Huang, Masafumi Tamura, Yi Chen, Melissa Woltkamp, Lee-Way Jin, Elisabeth M. Perchellet, Jean Pierre Perchellet, Peter K. Chiang, Ichiji Namatame, Hiroshi Tomoda

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 (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 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.

Original languageEnglish (US)
Pages (from-to)4795-4803
Number of pages9
JournalTetrahedron
Volume59
Issue number26
DOIs
StatePublished - Jun 23 2003
Externally publishedYes

Fingerprint

Pyrones
Adenine
Bioactivity
Cell death
Neurons
Cell Death
Derivatives
Toxicity
Esters
Carboxylation
Lead compounds
Benzopyrans
Mesylates
Amyloid beta-Protein Precursor
Alkylation
Carboxylic Acids
Amyloid
Aspartic Acid
Carbon Dioxide
Amides

Keywords

  • ACAT inhibitors
  • Alzheimer's disease
  • Amyloid-β peptides
  • APP C99-induced cell death
  • CETP inhibitors
  • Tricyclic pyrones

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Drug Discovery

Cite this

Hua, D. H., Huang, X., Tamura, M., Chen, Y., Woltkamp, M., Jin, L-W., ... Tomoda, H. (2003). Syntheses and bioactivities of tricyclic pyrones. Tetrahedron, 59(26), 4795-4803. https://doi.org/10.1016/S0040-4020(03)00687-2

Syntheses and bioactivities of tricyclic pyrones. / Hua, Duy H.; Huang, Xiaodong; Tamura, Masafumi; Chen, Yi; Woltkamp, Melissa; Jin, Lee-Way; Perchellet, Elisabeth M.; Perchellet, Jean Pierre; Chiang, Peter K.; Namatame, Ichiji; Tomoda, Hiroshi.

In: Tetrahedron, Vol. 59, No. 26, 23.06.2003, p. 4795-4803.

Research output: Contribution to journalArticle

Hua, DH, Huang, X, Tamura, M, Chen, Y, Woltkamp, M, Jin, L-W, Perchellet, EM, Perchellet, JP, Chiang, PK, Namatame, I & Tomoda, H 2003, 'Syntheses and bioactivities of tricyclic pyrones', Tetrahedron, vol. 59, no. 26, pp. 4795-4803. https://doi.org/10.1016/S0040-4020(03)00687-2
Hua DH, Huang X, Tamura M, Chen Y, Woltkamp M, Jin L-W et al. Syntheses and bioactivities of tricyclic pyrones. Tetrahedron. 2003 Jun 23;59(26):4795-4803. https://doi.org/10.1016/S0040-4020(03)00687-2
Hua, Duy H. ; Huang, Xiaodong ; Tamura, Masafumi ; Chen, Yi ; Woltkamp, Melissa ; Jin, Lee-Way ; Perchellet, Elisabeth M. ; Perchellet, Jean Pierre ; Chiang, Peter K. ; Namatame, Ichiji ; Tomoda, Hiroshi. / Syntheses and bioactivities of tricyclic pyrones. In: Tetrahedron. 2003 ; Vol. 59, No. 26. pp. 4795-4803.
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AU - Woltkamp, Melissa

AU - Jin, Lee-Way

AU - Perchellet, Elisabeth M.

AU - Perchellet, Jean Pierre

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