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.
Highlights
Chroman-4-one skeleton 1 is a core structure for a large group of plant metabolites called flavonoids, which possess many desirable biological activities including anticancer, antibacterial, and antioxidant properties [1,2]
3-methylidenechroman-4-ones were evaluated in terms of their cytotoxic activity with a carbonyl group present in 3-methylidenechroman-4-ones 7 is a structural motif found against in three human cancer cell lines: promyelocytic leukemia HL-60, NALM-6, and breast a large number of natural products, such as α-methylidene-γand δ-lactones
3-methylidenechroman-4-ones 14 were evaluated in terms of their cytotoxic activity against three human cancer cell lines: promyelocytic leukemia HL-60, NALM-6, and breast adenocarcinoma cell line MCF-7
Summary
Chroman-4-one skeleton 1 is a core structure for a large group of plant metabolites called flavonoids, which possess many desirable biological activities including anticancer, antibacterial, and antioxidant properties [1,2]. Bonducellin 5 was isolated from Caesalpina bonducella [3] and Eucomin 6 from Eucomis bicolor BAK (Liliaceae) [4] Both natural and synthetic 3-arylidenechroman-4-ones 4 display valuable biological activities. They are potent and selective monoamine oxidase-B (MAO-B) inhibitors [5,6] and possess anti-cholinesterase activity [7,8], what makes them good candidates for the treatment of various neurological diseases such as Alzheimer’s or Parkinson’s disease.
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