1. Novel Combretastatin-2-aminoimidazole Analogues as Potent Tubulin Assembly Inhibitors: Exploration of Unique Pharmacophoric Impact of Bridging Skeleton and Aryl Moiety.
- Author
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Chaudhary V, Venghateri JB, Dhaked HP, Bhoyar AS, Guchhait SK, and Panda D
- Subjects
- Apoptosis drug effects, Blotting, Western, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Cycle drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Female, Humans, Microtubules metabolism, Mitosis drug effects, Molecular Structure, Prodrugs chemistry, Structure-Activity Relationship, Tubulin metabolism, Tumor Cells, Cultured, Bibenzyls chemistry, Breast Neoplasms drug therapy, Imidazoles chemistry, Tubulin chemistry, Tubulin Modulators chemistry, Tubulin Modulators pharmacology
- Abstract
Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route involving atom economical arene C-H bond arylation. Interestingly, four compounds showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer cells much more efficiently than CA-4. It depolymerized microtubules, induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding of compound 12 to tubulin. The distinctive pharmacophoric features of the bridging motif as well as quinoline nucleus were explored. We noted also a valuable quality of compound 12 as a potential probe in characterizing new CA-4 analogues.
- Published
- 2016
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