The clinical success of Taxol and the promise of compounds like the combretastatins support the continued investigation of the a,b-tubulin heterodimer as a molecular target in cancer chemotherapy. Although colchicine remains the gold standard for probing tubulin structure, colchicine and its biaryl derivatives have not been thoroughly investigated for their anti-proliferative properties. In fact, 2-methoxy-5-(2,3,4-trimethoxyphenyl)cyclohepta-2,4,6-trien-1-one, the biaryl equivalent of colchicine, retains most of the anti-mitotic properties of colchicine itself. In this work, we investigated whether biaryl colchicinoids targeting the a,b-tubulin heterodimer may be viable agents for cancer chemotherapy. Towards further understanding of the SAR and therapeutic potential of this class, we have designed, synthesized, and evaluated 34 biaryl colchicinoids. We have discovered five agents with submicromolar activity in the lung (H520) and prostate (PC3) cell lines examined, and one compound that possesses an I50 for tubulin polymerization in the micromolar range using a high throughput polymerization assay. Overall, we will elaborate our synthetic methodology and discuss our SAR conclusions as we begin to address the question: "Is the trimethoxy motif on AC's core essential for biological activity?"
Back to Organic Chemistry Session III
Back to The 33rd Northeast Regional Meeting (July 14-17, 2005)