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Issue 9, 2016
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Synthesis and anticancer properties of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins

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Abstract

A simple and general strategy for the synthesis of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins has been developed. The elaborated synthetic protocol includes 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)- or Cs2CO3-promoted conjugate addition of enolizable ketones to 3-(diethoxyphosphoryl)coumarins followed by Horner–Wadsworth–Emmons reaction of the resulting 3-diethoxyphosphoryl-4-(2-oxoalkyl)-3,4-dihydrocoumarins with formaldehyde. For prochiral ketones, the corresponding α-methylene-δ-lactones were obtained as single syn-diastereoisomers. All α-methylene-δ-lactones were evaluated in vitro for their cytotoxic activity against two human leukemia cell lines, HL-60 and NALM-6, as well as the MCF-7 breast cancer cell line. One selected compound, 13h, was further tested in order to elucidate the mechanism behind its cytotoxic effect. In MCF-7 cells, this compound was shown to induce subG0/G1 cell cycle arrest, increased Bax and decreased Bcl-2 mRNA levels, and cause the dissipation of the mitochondrial membrane potential which indicated that it induced the intrinsic pathway of apoptosis.

Graphical abstract: Synthesis and anticancer properties of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins

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Supplementary files

Article information


Submitted
26 Feb 2016
Accepted
21 Jun 2016
First published
22 Jun 2016

Med. Chem. Commun., 2016,7, 1745-1758
Article type
Research Article

Synthesis and anticancer properties of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins

D. Deredas, K. Huben, A. Janecka, A. Długosz, D. K. Pomorska, M. Mirowski, U. Krajewska, T. Janecki and H. Krawczyk, Med. Chem. Commun., 2016, 7, 1745
DOI: 10.1039/C6MD00118A

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