Synthesis and cytotoxic activity of gamma-aryl substituted alpha-alkylidene-gamma-lactones and alpha-alkylidene-gamma-lactams.
A series of 5-aryl-3-alkylidenedihydrofuran-2(3H)-ones 6a-g'' and 11a,b as well as 5-aryl-3-methylidenepyrrolidin-2-ones 10a-c and 12 were synthesized starting from 4-aryl-2-diethoxyphosphoryl-4-oxobutanoates 3a-g. Reaction sequence includes reduction or reductive amination of the carbonyl group, lactonization or lactamization step and finally the Horner-Wadsworth-Emmons olefination of aldehydes using thus obtained 5-aryl-3-diethoxyphosphoryl-3,4-dihydrofuran-2(5H)-ones 5a-g'' or 5-aryl-3-diethoxyphosphorylpyrrolidin-2-ones 9a-c. Furanones 6 and 11, as well as pyrrolidinones 10 and 12, were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Several of the obtained furanones proved to be very potent against all three cell lines with IC(50) values lower than 6 microM. Structure-activity relationships of these compounds, as well as 5-alkyl or 5-arylmethyl-3-methylidenedihydrofuran-2(3H)-ones 13a-e, previously obtained in our laboratory, are discussed.
Albrecht
Anna
A
Institute of Organic Chemistry, Technical University of Łódź, Zeromskiego 116, 90-924 Łódź, Poland.
Koszuk
Jacek F
JF
Modranka
Jakub
J
Rózalski
Marek
M
Krajewska
Urszula
U
Janecka
Anna
A
Studzian
Kazimierz
K
Janecki
Tomasz
T
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D051379:Mice; D015394:Molecular Structure; D012015:Reference Standards; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007769:Lactams; D007783:Lactones