New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and antiproliferative activity of (−)-cleistenolide and analogues

[Display omitted] A stereoselective total synthesis of (−)-cleistenolide (1) from d-glucose has been achieved. This new approach for the synthesis of (−)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-l...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-07, Vol.26 (14), p.3318-3321
Main Authors: Benedeković, Goran, Kovačević, Ivana, Popsavin, Mirjana, Francuz, Jovana, Kojić, Vesna, Bogdanović, Gordana, Popsavin, Velimir
Format: Article
Language:English
Subjects:
Analogue synthesis
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antitumour δ-lactones
Cell Proliferation - drug effects
Cleistenolide
Cleistenolide mimics
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacology
Molecular Conformation
Pyrones - chemical synthesis
Pyrones - chemistry
Pyrones - pharmacology
SAR
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:[Display omitted] A stereoselective total synthesis of (−)-cleistenolide (1) from d-glucose has been achieved. This new approach for the synthesis of (−)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC50 0.02μM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized δ-lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.05.044