title: Synthesis of 4,4-Disubstituted 3-Methylidenechroman-2-ones as Potent Anticancer Agents.
abstract: The synthesis of a new library of 4,4-disubstituted 3-methylidene-3,4-dihydro-2H-chroman-2-ones applying Horner-Wadsworth-Emmons methodology for the construction of an exo-methylidene moiety is reported. Corresponding 3-diethoxyphosphorylchroman-2-ones were synthesized in a three-step reaction sequence consisting of O-methylation of ethyl 2-diethoxyphosphoryl-3-oxoalkanoates, followed by reaction of the obtained 2-diethoxyphosphoryl-3-methoxy-2-alkenoates with phenols or 1-naphthol. The resulting 3-diethoxyphosphorylochromen-2-ones proved to be effective Michael acceptors in reactions with various Grignard reagents. Preliminary biological evaluations showed that many of the synthesized 3-methylidenechroman-2-ones possess very high cytotoxic activity against NALM-6 and HL-60 cancer cell lines (IC50<1.0 μm) as well as high activity against the MCF-7 cancer cell line (IC50<10 μm). Furthermore, two of the highly active 3-methylidenechroman-2-ones with geminal methyl and ethyl substituents at position 4 showed promising therapeutic indexes of 10 and 13 in tests against human umbilical vein endothelial cells (HUVECs).
authors.affiliation: Institute of Organic Chemistry, Łódź University of Technology, Żeromskiego 116, 90-924, Łódź, Poland.|Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Łódź, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Jakubowski
authors.affiliation: Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215, Łódź, Poland.
authors.forename: Dorota K
authors.initials: DK
authors.lastname: Pomorska
authors.affiliation: Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215, Łódź, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Długosz
authors.affiliation: Department of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215, Łódź, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janecka
authors.affiliation: Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151, Łódź, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Krajewska
authors.affiliation: Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151, Łódź, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Różalski
authors.affiliation: Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151, Łódź, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Mirowski
authors.affiliation: Institute of Organic Chemistry, Łódź University of Technology, Żeromskiego 116, 90-924, Łódź, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bartosik
authors.affiliation: Institute of Organic Chemistry, Łódź University of Technology, Żeromskiego 116, 90-924, Łódź, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Janecki
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007536:Isomerism; D061986:MCF-7 Cells; D013329:Structure-Activity Relationship
chemical_list: C000622777:4-ethyl-4-methyl-3-methylidene-3,4-dihydro-2H-benzo(h)chromen-2-one; C000622776:4-ethyl-5,7-dimethoxy-4-methyl-3-methylidene-3,4-dihydro-2H-chromen-2-one; D000970:Antineoplastic Agents; D003374:Coumarins; D016190:Carboplatin
keywords: 3-methylidenechroman-2-ones; Horner-Wadsworth-Emmons olefination; Michael addition; cytotoxicity; phosphorylated heterocycles