Synthesis of novel 4,4-disubstituted 3-methylidenechroman-2-ones as potent anticancer agents.

Synthesis of novel 4,4-disubstituted 3-methylidenechroman-2-ones as potent anticancer agents.

ChemMedChem. 2017 Mar 04;:

Authors: Jakubowski R, Pomorska D, Długosz A, Janecka A, Krajewska U, Różalski M, Mirowski M, Bartosik T, Janecki T

Abstract
The synthesis of new library of 4,4-disubstituted 3-methylidene-3,4-dihydro-2H-chroman-2-ones applying Horner-Wadsworth-Emmons methodology for the construction of egzo-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 obtained 2-diethoxyphosphoryl-3-methoxy-2-alkenoates with phenols or 1-naphthol. Obtained 3-diethoxyphosphorylochromen-2-ones proved to be effective Michael acceptors in the reaction with various Grignard reagents. Preliminary biological evaluation 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 < 1.0 mM) as well as high activity against MCF-7 cancer cell line (IC50 < 10 mM). Furthermore, two of the highly active 3-methylidenechroman-2-ones with geminal methyl and ethyl substituents in position 4 showed promising therapeutic index of 10 and 13 when tested against human umbilical vein endothelial cells (HUVEC).

PMID: 28258688 [PubMed - as supplied by publisher]

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