Novel Synthesis, Cytotoxic Evaluation, and Structure−Activity Relationship Studies of a Series of α-Alkylidene-γ-lactones and Lactams

5-Alkyl- and 5-arylalkyl-3-methylenedihydrofuran-2-ones 13a − e, 3-alkylidenedihydrofuran-2-ones 18a − c, and 3-methylenepyrrolidin-2-ones 16a − e were synthesized utilizing ethyl 2-diethoxyphosphoryl-4-nitroalkanoates 9a − e as common intermediates. All obtained compounds were tested against L-1210...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-05, Vol.48 (10), p.3516-3521
Main Authors: Janecki, Tomasz, Błaszczyk, Edyta, Studzian, Kazimierz, Janecka, Anna, Krajewska, Urszula, Różalski, Marek
Format: Article
Language:English
Subjects:
4-Butyrolactone - analogs & derivatives
4-Butyrolactone - chemical synthesis
4-Butyrolactone - chemistry
4-Butyrolactone - pharmacology
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Drug Screening Assays, Antitumor
General aspects
Humans
Lactams - chemical synthesis
Lactams - chemistry
Lactams - pharmacology
Lactones - chemical synthesis
Lactones - chemistry
Lactones - pharmacology
Medical sciences
Pharmacology. Drug treatments
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Structure-Activity Relationship
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Summary:5-Alkyl- and 5-arylalkyl-3-methylenedihydrofuran-2-ones 13a − e, 3-alkylidenedihydrofuran-2-ones 18a − c, and 3-methylenepyrrolidin-2-ones 16a − e were synthesized utilizing ethyl 2-diethoxyphosphoryl-4-nitroalkanoates 9a − e as common intermediates. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemia cells. The highest cytotoxic activity was observed for 3-methylenefuranones 13d,e bearing benzyl or 3,4-dimethoxyphenylmethyl substituents at position 5, with IC50 values of 5.4 and 6.0 μM, respectively. Contrary to the literature reports, no enhancement in activity due to the presence of a hydroxy group was found when the cytotoxicity of furanones 13a,b,d and 5-(1‘-hydroxyalkyl)-3-methylenedihydrofuran-2-ones 6a,b,d was compared. The anticancer activity of pyrrolidinones 16a − e and 3-alkylidenefuranones 18a − c was much weaker than that of furanones 13a − e.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm048970a