High Content Screening of Diverse Compound Libraries Identifies Potent Modulators of Tubulin Dynamics

Tubulin modulating agents such as the taxanes are among the most effective antimitotic cancer drugs, although resistance and toxicity present significant problems in their clinical use. However, most tubulin modulators are derived from complex natural products, which can make modification of their structure to address these problems difficult. Here, we report the discovery of new antimitotic compounds with simple structures that can be rapidly synthesized, through the phenotypic screening of a diverse compound library for the induction of mitotic arrest. We first identified a compound, which induced mitotic arrest in human cells at submicromolar concentrations. Its simple structure enabled rapid exploration of activity, defining a biphenylacetamide moiety required for activity, A family of analogues was synthesized, yielding optimized compounds that caused mitotic arrest and cell death in the low nanomolar range, comparable to clinically used antimitotic agents. These compounds can be synthesized in 1–3 steps and good yields. We show that one such compound targets tubulin, partially inhibiting colchicine but not vinblastine binding, suggesting that it acts allosterically to the known colchicine-binding site. Thus, our results exemplify the use of phenotypic screening to identify novel antimitotic compounds from diverse chemical libraries and characterize a family of biphenylacetamides (biphenabulins) that show promise for further development

Additional file 2: of Antiplasmodial and trypanocidal activity of violacein and deoxyviolacein produced from synthetic operons

Figure S2. Cytotoxicity of deoxyviolacein and violacein to HepG2 cells. Morphological changes of HepG2 cells treated with 0.8 to 100 uM of deoxyviolacein and violacein. Figure S3. Cytotoxicity of deoxyviolacein and violacein to CHO-745 cells. Morphological changes of CHO-745 cells treated with 0.8 to 100 uM of deoxyviolacein and violacein. (PDF 4205 kb

Additional file 1: of Antiplasmodial and trypanocidal activity of violacein and deoxyviolacein produced from synthetic operons

Figure S1. Chemical structure ( www.chemspider.com ) and 1H spectra of Violacein and Deoxyviolacein. Chemical structure ( www.chemspider.com ) and 1H spectra of Violacein and Deoxyviolacein. (PDF 216 kb