Synthesis and biological evaluation of ¦Á-methylidene-¦Ä-lactones with 3,4-dihydrocoumarin skeleton
详细信息 查看全文
- 作者：Jakub Modranka ; Anna Albrecht ; Rafa? Jakubowski ; Henryk Krawczyk ; Marek R¨®?alski ; Urszula Krajewska ; Anna Janecka ; Anna Wyr?bska ; Barbara R¨®?alska ; Tomasz Janecki
- 关键词：¦Á-Methylidene-¦Ä-lactones ; Cytotoxicity ; Antimicrobial activity ; Structure&ndash ; activity relationship
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2012
- 出版时间：15 August, 2012
- 年：2012
- 卷：20
- 期：16
- 页码：5017-5026
- 全文大小：774 K
文摘
A series of new 3-methylidenechroman-2-ones bearing various aromatic moieties and various substituents at position 4 were synthesized in a three step reaction sequence. Friedel-Crafts alkylation of phenols or naphthols using ethyl 3-methoxy-2-diethoxyphosphorylacrylate in the presence of trifluoromethanesulphonic acid gave 3-diethoxyphosphorylchromen-2-ones. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to give adducts which were finally used as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. All obtained 3-methylidenechroman-2-ones were tested against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer and HT-29 colon cancer adenocarcinomas. Several obtained methylidenechromanones displayed high cytotoxic activity with IC50 values below 1 ¦ÌM, mainly against leukemia and MCF-7 cell lines. Investigation of structure-activity relationships revealed that the presence of additional, ortho-fused benzene ring and n-butyl or i-propyl group in position 4 enhances the activity. Selected methylidenechromanones were also tested on normal human umbilical vein endothelial cells (HUVEC) and chromanone 14o was found to be eightfold more toxic against MCF-7 than normal cells. Furthermore, antimicrobial assays revealed that chromanone 14n is highly active and bactericidal at concentration equal to MIC or 2MIC against nosocomial and community-associated staphylococci (MRSA) which are resistant to most or all available therapeutic classes of antimicrobial drugs.