4-Methylideneisoxazolidin-5-ones—A new class of α-methylidene-γ-lactones with high cytostatic activity

A series of 4-methylideneisoxazolidin-5-ones was synthesized and their cytostatic activity against L-1210, HL-60, and NALM-6 leukemia cell lines was evaluated. The most potent analogues had IC 50 < 1 μM. A novel, general method of synthesis of 4-methylideneisoxazolidin-5-ones 10 is described. The...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006-03, Vol.16 (5), p.1430-1433
Main Authors: Janecki, Tomasz, Wąsek, Tomasz, Różalski, Marek, Krajewska, Urszula, Studzian, Kazimierz, Janecka, Anna
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cytostatic activity
General aspects
Horner–Wadsworth–Emmons olefination
Humans
Inhibitory Concentration 50
Isoxazolidin-5-ones
Lactones - chemical synthesis
Lactones - chemistry
Lactones - classification
Lactones - pharmacology
Leukemia - pathology
Medical sciences
Molecular Structure
Oxazoles - chemical synthesis
Oxazoles - chemistry
Oxazoles - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
α-Methylidene-β-lactones
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Summary:A series of 4-methylideneisoxazolidin-5-ones was synthesized and their cytostatic activity against L-1210, HL-60, and NALM-6 leukemia cell lines was evaluated. The most potent analogues had IC 50 < 1 μM. A novel, general method of synthesis of 4-methylideneisoxazolidin-5-ones 10 is described. The target compounds were synthesized starting from ethyl 2-diethoxyphosphoryl-2-alkenoates 6 or dicyclohexylammonium 4-diethoxyphosphoryl-2-alkenoates 7. Addition of N-methylhydroxylamine hydrochloride to these Michael acceptors, lactonization to 4-diethoxyphosphorylisoxazolidin-5-ones 9, and Horner–Wadsworth–Emmons olefination of formaldehyde using 9 gave the title isoxazolidinones 10. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemia cell lines. Several isoxazolidinones 10 were found to be very potent with IC 50 < 1 μM. The highest cytostatic activity against HL-60 was observed for 10a and against NALM-6 for 10b with IC 50 values of 0.74 and 0.34 μM, respectively.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.11.032