Synthesis and Evaluation of 1,5-Disubstituted Tetrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative and Antitumor Activity
Citations Over TimeTop 10% of 2011 papers
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.
Related Papers
- → Combretastatin A-4 Analogues as Antimitotic Antitumor Agents(2003)318 cited
- → Combretastatin A-4 Analogs as Anticancer Agents(2007)152 cited
- → Natural Products As Antimitotic Agents(2014)57 cited
- → Antimitotic activity of structurally simplified biaryl analogs of the anticancer agents colchicine and combretastatin A4(2014)15 cited
- → Antimitotic activity of diaryl compounds with structural features resembling combretastatin A-4(1998)19 cited