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 | Jian-Xin Duan, Xiaohong Cai, Fanying Meng, Leslie Lan, Charles Hart, Mark Matteucci |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 50
Issue 5
Pg. 1001-6
(Mar 08 2007)
ISSN: 0022-2623 [Print] United States |
PMID | 17286393
(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)
|