Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids.
The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses.
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Agnieszka
A
Ambrożak
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Christian
C
Steinebach
Clinical Pharmacology Program, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Erin R
ER
Gardner
Molecular Pharmacology Section, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
Shaunna L
SL
Beedie
Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121, Bonn, Germany.
Gregor
G
Schnakenburg
Molecular Pharmacology Section, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
William D
WD
Figg
Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Michael
M
Gütschow
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D010797:Phthalimides / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000737:chemistry
D020533:Angiogenesis Inhibitors; D001463:Barbiturates; D010797:Phthalimides; C037431:phthalimide; D013792:Thalidomide; C032232:barbituric acid
angiogenesis; barbituric acids; phthalimides; tetrafluorobenzamides; tetrafluorophthalimides