Synthesis and anticancer properties of 3-methylene-4-(2-oxoalkyl)-3,4-dihydrocoumarins
| Autor: | Angelika Długosz, Henryk Krawczyk, Tomasz Janecki, Dorota K. Pomorska, Marek Mirowski, Urszula Krajewska, Krzysztof Huben, Anna Janecka, Dariusz Deredas |
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| Rok vydání: | 2016 |
| Předmět: |
Pharmacology
Membrane potential 010405 organic chemistry Stereochemistry Organic Chemistry Pharmaceutical Science 010402 general chemistry 01 natural sciences Biochemistry In vitro 0104 chemical sciences chemistry.chemical_compound chemistry Apoptosis Cell culture Drug Discovery Molecular Medicine Cytotoxic T cell Methylene G1 phase Conjugate |
| Zdroj: | MedChemComm. 7:1745-1758 |
| ISSN: | 2040-2511 2040-2503 |
| DOI: | 10.1039/c6md00118a |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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