title: 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.
authors.affiliation: Threshold Pharmaceuticals, 1300 Seaport Boulevard, Redwood City, California 94063, USA. jduan@thresholdpharm.com
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Duan
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cai
authors.forename: Fanying
authors.initials: F
authors.lastname: Meng
authors.forename: Leslie
authors.initials: L
authors.lastname: Lan
authors.forename: Charles
authors.initials: C
authors.lastname: Hart
authors.forename: Mark
authors.initials: M
authors.lastname: Matteucci
mesh_terms: D000114:Acetylene / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D045744:Cell Line, Tumor; D003078:Colchicine / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007191:Indazoles; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C058728:fosbretabulin; D000114:Acetylene; D003078:Colchicine