Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors.
The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 microM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely related to this lead, no other compound was found to be active in the tubulin polymerization assay. However, by screening in the in vivo chick embryo assay 10 was identified as a potent angiogenesis inhibitor indicating an alternative target. Indeed, molecular modeling studies suggest a reasonable binding mode of 10 at the ATP-binding site of the model kinase CDK2. Motivated by these results, analogues of 10 were screened for inhibitory activity in a panel of 12 selected protein kinases and a high affinity of 10 to VEGF-R2 was found showing an IC50 of 2.5 nM. Structure-activity relationships (SAR) for this compound series with the isolated enzyme and equivalent antiangiogenic activity in the chick embryo assay are presented herein.
Peifer
Christian
C
Department of Pharmacy, Johannes Gutenberg-University, Staudingerweg 5, D-55099 Mainz, Germany.
Stoiber
Thomas
T
Unger
Eberhard
E
Totzke
Frank
F
Schächtele
Christoph
C
Marmé
Dieter
D
Brenk
Ruth
R
Klebe
Gerhard
G
Schollmeyer
Dieter
D
Dannhardt
Gerd
G
D000255:Adenosine Triphosphate / Q000737:chemistry; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002642:Chick Embryo; D015195:Drug Design; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry
C509264:3-(indole-3-yl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole-2,5-dione; D020533:Angiogenesis Inhibitors; D007211:Indoles; D008301:Maleimides; D011758:Pyrroles; D000255:Adenosine Triphosphate; D040301:Vascular Endothelial Growth Factor Receptor-2