Synthesis of 4,4‐Disubstituted 3‐Methylidenechroman‐2‐ones as Potent Anticancer Agents

The synthesis of a new library of 4,4‐disubstituted 3‐methylidene‐3,4‐dihydro‐2H‐chroman‐2‐ones applying Horner–Wadsworth–Emmons methodology for the construction of an exo‐methylidene moiety is reported. Corresponding 3‐diethoxyphosphorylchroman‐2‐ones were synthesized in a three‐step reaction seque...

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Published in:ChemMedChem 2017-04, Vol.12 (8), p.599-605
Main Authors: Jakubowski, Rafał, Pomorska, Dorota K., Długosz, Angelika, Janecka, Anna, Krajewska, Urszula, Różalski, Marek, Mirowski, Marek, Bartosik, Tomasz, Janecki, Tomasz
Format: Article
Language:English
Subjects:
3-methylidenechroman-2-ones
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Carboplatin - pharmacology
Coumarins - chemical synthesis
Coumarins - chemistry
Coumarins - pharmacology
cytotoxicity
HL-60 Cells
Horner–Wadsworth–Emmons olefination
Human Umbilical Vein Endothelial Cells
Humans
Isomerism
MCF-7 Cells
Michael addition
phosphorylated heterocycles
Structure-Activity Relationship
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Summary:The synthesis of a new library of 4,4‐disubstituted 3‐methylidene‐3,4‐dihydro‐2H‐chroman‐2‐ones applying Horner–Wadsworth–Emmons methodology for the construction of an exo‐methylidene moiety is reported. Corresponding 3‐diethoxyphosphorylchroman‐2‐ones were synthesized in a three‐step reaction sequence consisting of O‐methylation of ethyl 2‐diethoxyphosphoryl‐3‐oxoalkanoates, followed by reaction of the obtained 2‐diethoxyphosphoryl‐3‐methoxy‐2‐alkenoates with phenols or 1‐naphthol. The resulting 3‐diethoxyphosphorylochromen‐2‐ones proved to be effective Michael acceptors in reactions with various Grignard reagents. Preliminary biological evaluations showed that many of the synthesized 3‐methylidenechroman‐2‐ones possess very high cytotoxic activity against NALM‐6 and HL‐60 cancer cell lines (IC50
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700080