Synthesis of 4, 4‐Disubstituted 3‐Methylidenechroman‐2‐ones as Potent Anticancer Agents. (22nd March 2017)

• Record Type: Journal Article
• Authors: Jakubowski, Rafał; Pomorska, Dorota K.; Długosz, Angelika; Janecka, Anna; Krajewska, Urszula; Różalski, Marek; Mirowski, Marek; Bartosik, Tomasz; Janecki, Tomasz
• Is Part Of: ChemMedChem. Volume 12:Number 8(2017)
• Page Start: 599
• Page End: 605
• Publication Date: 2017-03-22
• Subjects: 3-methylidenechroman-2-ones -- cytotoxicity -- Horner–Wadsworth–Emmons olefination -- Michael addition -- phosphorylated heterocycles; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700080
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The synthesis of a new library of 4, 4‐disubstituted 3‐methylidene‐3, 4‐dihydro‐2 H ‐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). Abstract : First place, position 4 : The efficient synthesis of a new library of 4, 4‐disubstituted 3‐methylidene‐3, 4‐dihydro‐2 H ‐chroman‐2‐ones using Horner–Wadsworth–Emmons methodology is described. These compounds can be regarded as molecular hybrids containing two pharmacophore units: an α‐methylidene‐δ‐lactone moiety and a chroman‐2‐one skeleton. Cytotoxicity tests revealed that many of these chroman‐2‐ones are highly cytotoxic against NALM‐6 and HL‐60 cancer cell lines (IC50 <1.0 μm ) and have high activity against the MCF‐7 cancer cell line (IC50 <10 μm ).