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Potent antitubulin tumor cell cytotoxins based on 3-aroyl indazoles.

Abstract
A series of 3-aroyl indazoles was synthesized. Modification of the C-7 position resulted in a significant structure-activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastatin A4 (CA-4), showing single digit nM IC50 values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds. Competition binding experiments employing [3H]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site.
AuthorsJian-Xin Duan, Xiaohong Cai, Fanying Meng, Leslie Lan, Charles Hart, Mark Matteucci
JournalJournal of medicinal chemistry (J Med Chem) Vol. 50 Issue 5 Pg. 1001-6 (Mar 08 2007) ISSN: 0022-2623 [Print] United States
PMID17286393 (Publication Type: Journal Article)
Chemical References
  • Indazoles
  • Stilbenes
  • Tubulin
  • Tubulin Modulators
  • fosbretabulin
  • Acetylene
  • Colchicine
Topics
  • Acetylene (chemistry)
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cattle
  • Cell Line, Tumor
  • Colchicine (chemistry)
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Humans
  • Indazoles (chemical synthesis, chemistry, pharmacology)
  • Radioligand Assay
  • Stilbenes (chemistry, pharmacology)
  • Structure-Activity Relationship
  • Tubulin (chemistry)
  • Tubulin Modulators (chemical synthesis, chemistry, pharmacology)

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