Vascular disrupting activity of tubulin-binding 1,5-diaryl-1H-imidazoles.
Highly cytotoxic 1,5-diaryl-1H-imidazoles were studied to clarify the relationship between cytotoxicity and activity as vascular disrupting agents (VDA). All the compounds disorganized the tubulin cytoskeleton, affected endothelial cell morphology and capillary formation in vitro, and caused vessel shutdown and tumor necrosis in vivo, thus confirming their vascular disrupting properties. Nonetheless, the substitution patterns on the imidazole ring, responsible for greater interaction energy with tubulin and higher cytotoxicity, were not associated to greater vascular disrupting activity.
Bonezzi
Katiuscia
K
Department of Oncology, Mario Negri Institute for Pharmacological Research, via Gavazzeni 11, 24125 Bergamo, Italy.
Taraboletti
Giulia
G
Borsotti
Patrizia
P
Bellina
Fabio
F
Rossi
Renzo
R
Giavazzi
Raffaella
R
D000818:Animals; D001665:Binding Sites; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D006851:Hydrochloric Acid / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007536:Isomerism; D051379:Mice; D009369:Neoplasms / Q000098:blood supply; D014404:Tubulin / Q000378:metabolism*
D007093:Imidazoles; D014404:Tubulin; D006851:Hydrochloric Acid