4-Methylideneisoxazolidin-5-ones--a new class of alpha-methylidene-gamma-lactones with high cytostatic activity.
A novel, general method of synthesis of 4-methylideneisoxazolidin-5-ones 10 is described. The target compounds were synthesized starting from ethyl 2-diethoxyphosphoryl-2-alkenoates 6 or dicyclohexylammonium 4-diethoxyphosphoryl-2-alkenoates 7. Addition of N-methylhydroxylamine hydrochloride to these Michael acceptors, lactonization to 4-diethoxyphosphorylisoxazolidin-5-ones 9, and Horner-Wadsworth-Emmons olefination of formaldehyde using 9 gave the title isoxazolidinones 10. All obtained compounds were tested against L-1210, HL-60, and NALM-6 leukemia cell lines. Several isoxazolidinones 10 were found to be very potent with IC(50)<1 microM. The highest cytostatic activity against HL-60 was observed for 10a and against NALM-6 for 10b with IC(50) values of 0.74 and 0.34 microM, respectively.
Janecki
Tomasz
T
Institute of Organic Chemistry, Technical University of Łódź, 90-924 Łódź, Poland. tjanecki@p.lodz.pl
Wasek
Tomasz
T
Rózalski
Marek
M
Krajewska
Urszula
U
Studzian
Kazimierz
K
Janecka
Anna
A
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D007938:Leukemia / Q000473:pathology*; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007783:Lactones; D010080:Oxazoles