Abstract
Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Apoptosis / drug effects
-
Caspases / metabolism
-
Cell Line, Tumor
-
Cell Proliferation / drug effects*
-
Drug Resistance, Multiple
-
Drug Resistance, Neoplasm
-
Enzyme Activation
-
Humans
-
Membrane Potential, Mitochondrial / drug effects
-
Mice
-
Mice, Nude
-
Models, Molecular
-
Neoplasm Transplantation
-
Stilbenes / chemistry*
-
Structure-Activity Relationship
-
Tetrazoles / chemical synthesis*
-
Tetrazoles / chemistry
-
Tetrazoles / pharmacology
-
Transplantation, Heterologous
-
Tubulin Modulators / chemical synthesis*
-
Tubulin Modulators / chemistry
-
Tubulin Modulators / pharmacology
Substances
-
1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-tetrazole
-
ATP Binding Cassette Transporter, Subfamily B, Member 1
-
Antineoplastic Agents
-
Stilbenes
-
Tetrazoles
-
Tubulin Modulators
-
Caspases
-
fosbretabulin