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Synthesis of 4,4‐Disubstituted 3‐Methylidenechroman‐2‐ones as Potent Anticancer Agents
Author(s) -
Jakubowski Rafał,
Pomorska Dorota K.,
Długosz Angelika,
Janecka Anna,
Krajewska Urszula,
Różalski Marek,
Mirowski Marek,
Bartosik Tomasz,
Janecki Tomasz
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700080
Subject(s) - moiety , chemistry , stereochemistry , reagent , cell culture , ic50 , phenols , michael reaction , methylation , cancer cell lines , cancer cell , combinatorial chemistry , in vitro , organic chemistry , cancer , biochemistry , dna , biology , genetics , catalysis
The synthesis of a new library of 4,4‐disubstituted 3‐methylidene‐3,4‐dihydro‐2 H ‐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 (IC 50 <1.0 μ m ) as well as high activity against the MCF‐7 cancer cell line (IC 50 <10 μ m ). Furthermore, two of the highly active 3‐methylidenechroman‐2‐ones with geminal methyl and ethyl substituents at position 4 showed promising therapeutic indexes of 10 and 13 in tests against human umbilical vein endothelial cells (HUVECs).