title: Combretastatin A-4 derived imidazoles show cytotoxic, antivascular, and antimetastatic effects based on cytoskeletal reorganisation.
abstract: BACKGROUND
  Combretastatin A-4 (CA-4) is a natural cis-stilbene which interferes with the cellular tubulin dynamics and which selectively destroys tumour blood vessels. Its pharmacological shortcomings such as insufficient chemical stability, water solubility, and cytotoxicity can be remedied by employing its imidazole derivatives.
  
  
  METHODS
  We studied 11 halogenated imidazole derivatives of CA-4 for their effects on the microtubule and actin cytoskeletons of cancer and endothelial cells and on the propensity of these cells to migrate across tissue barriers or to form blood vessel-like tubular structures.
  
  
  RESULTS
  A series of N-methyl-4-aryl-5-(4-ethoxyphenyl)-imidazoles proved far more efficacious than the lead CA-4 in growth inhibition assays against CA-4-resistant HT-29 colon carcinoma cells and generally more selective for cancer over nonmalignant cells. Et-brimamin (6), the most active compound, inhibited the growth of various cancer cell lines with IC50 (72 h) values in the low nanomolar range. Active imidazoles such as 6 reduced the motility and invasiveness of cancer cells by initiating the formation of actin stress fibres and focal adhesions as a response to the extensive microtubule disruption. The antimetastatic properties were ascertained in 3D-transwell migration assays which simulated the transgression of highly invasive melanoma cells through the extracellular matrix of solid tumours and through the endothelium of blood vessels. The studied imidazoles exhibited vascular-disrupting effects also against tumour xenografts that are refractory to CA-4. They were also less toxic and better tolerated by mice.
  
  
  CONCLUSIONS
  We deem the new imidazoles promising drug candidates for combination regimens with antiangiogenic VEGFR inhibitors.
authors: Organic Chemistry Laboratory, University Bayreuth, Universitaetsstrasse 30, 95440, Bayreuth, Germany.
authors: Katharina
authors: K
authors: Mahal
authors: Bernhard
authors: B
authors: Biersack
authors: Henrike
authors: H
authors: Caysa
authors: Rainer
authors: R
authors: Schobert
authors: Thomas
authors: T
authors: Mueller
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D003094:Collagen / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D004338:Drug Combinations; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007797:Laminin / Q000494:pharmacology; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011509:Proteoglycans / Q000494:pharmacology; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007093:Imidazoles; D007797:Laminin; D011509:Proteoglycans; D013267:Stilbenes; C000610583:brimamin; C059485:matrigel; C029899:imidazole; D003094:Collagen; C058728:fosbretabulin