Exploring Natural Product Chemistry and Biology with Multicomponent Reactions. 5. Discovery of a Novel Tubulin-Targeting Scaffold Derived from the Rigidin Family of Marine Alkaloids
| Autor: | Nikolai M. Evdokimov, Snezna Rogelj, Anntherese E. Romero, Charles B. Shuster, Laetitia Moreno Y Banuls, Tania Betancourt, Isaiah Otero, Kathryn Hayden, Ernest Hamel, Shi-Long Lu, Igor V. Magedov, Liliya V. Frolova, Alexander Kornienko, Shiva K. Rastogi, Ross W.R. Smith, Robert Kiss, Menuka Karki |
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| Rok vydání: | 2013 |
| Předmět: |
Spectrometry
Mass Electrospray Ionization Magnetic Resonance Spectroscopy Article HeLa Structure-Activity Relationship chemistry.chemical_compound Alkaloids Tubulin Microtubule Drug Discovery Humans Colchicine Structure–activity relationship Biological Products Natural product biology biology.organism_classification In vitro chemistry Biochemistry Cancer cell biology.protein Molecular Medicine HeLa Cells |
| Zdroj: | Journal of Medicinal Chemistry. 56:6886-6900 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400711t |
| Popis: | We developed synthetic chemistry to access the marine alkaloid rigidins and over 40 synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine, and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibited nanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases, and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerization and disorganized microtubules in live HeLa cells. Experiments evaluating the effects of the 7-deazahypoxanthines on the binding of [(3)H]colchicine to tubulin identified the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fight cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have significant potential as new anticancer agents. |
| Databáze: | OpenAIRE |
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