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. 2019 May 15;24(10):1868.
doi: 10.3390/molecules24101868.

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

Jacek Kędzia  1 , Tomasz Bartosik  2 , Joanna Drogosz  3 , Anna Janecka  4 , Urszula Krajewska  5 , Tomasz Janecki  6
Affiliations

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

Jacek Kędzia et al. Molecules. .

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 (14a-o) 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.

Keywords: 3-methylidenechroman-4-ones; Horner–Wadsworth–Emmons olefination; Michael addition; apoptosis; cancer cell lines.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Structure and representative examples of homoisoflavonoids.
Scheme 1
Scheme 1
Synthesis of 3-diethoxyphosphorylchromen-4-ones 12a–c.
Scheme 2
Scheme 2
Synthesis of Michael adducts 13a–o.
Figure 2
Figure 2
Half-chair conformation of trans- and cis-13a–o and characteristic 3JH2-H3, 3JH2-P and 3JC(R3)-P coupling constants.
Figure 3
Figure 3
Two main resonance structures involved in the resonance-assisted hydrogen bond (RAHB) in 3-diethoxyphosphoryl-2H-chromen-4-oles.
Scheme 3
Scheme 3
Synthesis of 3-methylidenechroman-4-ones 14a–o.
Figure 4
Figure 4
Effect of 14d on induction of apoptosis in NALM-6 cells. (A) The cytotoxic activity of 14d on NALM-6 cells after 24 h incubation; (B) Quantitative analysis of apoptosis by flow cytometry. The data are presented as mean ± SEM of three independent experiments. Statistical significance was determined using one-way ANOVA and a post-hoc multiple comparison Student–Newman–Keuls test. **** p < 0.0001; *** p < 0.001; ** p < 0.01; ns—not statistically significant. (C) Representative results of cell apoptosis obtained by Annexin V and PI staining using flow cytometry in NALM-6 cells untreated (control) or treated with 14d at IC50 and 2 IC50 concentrations for 24 h.
Figure 5
Figure 5
Activity of caspase 3, 8 and 9 in HL-60 cells after 6 h treatment with analog 14d at 1.25 µM (IC50) and 2.5 µM (2IC50) concentrations. Results are expressed as mean ± SEM of triplicate experiment. Statistical significance was assessed using one-way ANOVA and a post-hoc multiple comparison Student–Newman–Keuls test; *** p < 0.001; ** p < 0.01; * p < 0.05.
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