title: Synthesis and biological evaluation with plant cells of new fosmidomycin analogues containing a benzoxazolone or oxazolopyridinone ring.
abstract: Fosmidomycin, 3-(N-formyl-N-hydroxyamido) propylphosphonic acid sodium salt, is an efficient inhibitor of 1-deoxy-D-xylulose-5-phosphate (DOXP) reductoisomerase, the second enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway notably present in Plasmodium species. We have synthesized a new series of analogues of fosmidomycin, containing a benzoxazolone, benzoxazolethione or oxazolopyridinone ring. As the MEP pathway is involved in the biosynthesis of all isoprenoids, accumulation of ajmalicine in Catharanthus roseus cells was chosen as a marker of monoterpenoid indole alkaloid (MIA) production. None of the twelve studied phosphonic esters 3 and phosphonic acids 4 affected periwinkle cell growth, but some of them (3c, 3e, 3g and 3h) showed a significant inhibition of ajmalicine accumulation: 45-85% at 125 microM. Surprisingly, this effect disappeared by conversion of 3c and 3g into the corresponding acids 4c and 4g, respectively.
authors.affiliation: EA 2106 Biomolécules et Biotechnologies Végétales, Université de Tours, UFR Sciences Pharmaceutiques, 37200 Tours, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Courtois
authors.forename: Zoia
authors.initials: Z
authors.lastname: Mincheva
authors.forename: Françoise
authors.initials: F
authors.lastname: Andreu
authors.forename: Marc
authors.initials: M
authors.lastname: Rideau
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Viaud-Massuard
mesh_terms: D001583:Benzoxazoles / Q000737:chemistry*; D030008:Catharanthus / Q000166:cytology* / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry*; D011728:Pyridones / Q000737:chemistry*; D046948:Secologanin Tryptamine Alkaloids / Q000037:antagonists & inhibitors / Q000378:metabolism; D013871:Thiones / Q000737:chemistry
chemical_list: D001583:Benzoxazoles; D010080:Oxazoles; D011728:Pyridones; D046948:Secologanin Tryptamine Alkaloids; D013871:Thiones; C508121:benzoxazolethione; C508120:oxazolopyridinone; D005578:Fosfomycin; C017057:benzoxazolone; C005709:raubasine; C024640:fosmidomycin