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Synthesis and Cytotoxic Evaluation of 3-Methylidenechroman-4-ones

1
Institute of Organic Chemistry, Lodz University of Technology, Żeromskiego 116, 90-924 Łódź, Poland
2
Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215 Łódź, Poland
3
Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź, Poland
*
Author to whom correspondence should be addressed.
Academic Editors: Carla Boga and Gabriele Micheletti
Molecules 2019, 24(10), 1868; https://doi.org/10.3390/molecules24101868
Received: 26 April 2019 / Revised: 9 May 2019 / Accepted: 11 May 2019 / Published: 15 May 2019
(This article belongs to the Special Issue Design and Synthesis of Organic Molecules as Antineoplastic Agents)
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Abstract

In the search for new anticancer agents, a library of variously substituted 3-methylidenechroman-4-ones was synthesized using Horner–Wadsworth–Emmons methodology. Acylation of diethyl methylphosphonate with selected ethyl salicylates furnished 3-diethoxyphosphorylchromen-4-ones which were next used as Michael acceptors in the reaction with various Grignard reagents. The adducts were obtained as the mixtures of trans and cis diastereoisomers along with a small amount of enol forms. Their relative configuration and preferred conformation were established by NMR analysis. The adducts turned up to be effective Horner–Wadsworth–Emmons reagents giving 2-substituted 3-methylidenechroman-4-ones, which were then tested for their possible cytotoxic activity against two leukemia cell lines, HL-60 and NALM-6, and against MCF-7 breast cancer cell line. All new compounds (14ao) were highly cytotoxic for the leukemic cells and showed a moderate or weak effect on MCF-7 cells. Analog 14d exhibited the highest growth inhibitory activity and was more potent than carboplatin against HL-60 (IC50 = 1.46 ± 0.16 µM) and NALM-6 (IC50 = 0.50 ± 0.05 µM) cells. Further tests showed that 14d induced apoptosis in NALM-6 cells, which was mediated mostly through the extrinsic pathway. View Full-Text
Keywords: 3-methylidenechroman-4-ones; Michael addition; Horner–Wadsworth–Emmons olefination; cancer cell lines; apoptosis 3-methylidenechroman-4-ones; Michael addition; Horner–Wadsworth–Emmons olefination; cancer cell lines; apoptosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Kędzia, J.; Bartosik, T.; Drogosz, J.; Janecka, A.; Krajewska, U.; Janecki, T. Synthesis and Cytotoxic Evaluation of 3-Methylidenechroman-4-ones. Molecules 2019, 24, 1868.

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