1. 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
- Author
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Frolova, Liliya V, Magedov, Igor I.V., Romero, Anntherese A.E., Karki, Menuka, Otero, Isaiah, Hayden, Kathryn, Evdokimov, Nikolai N.M., Banuls, Laetitia Moreno Y, Rastogi, Shiva S.K., Smith, Ross W.R., Lu, Shi-Long, Kiss, Robert, Shuster, Charles C.B., Hamel, Ernest, Betancourt, Tania, Rogelj, Snezna, Kornienko, Alexander, Frolova, Liliya V, Magedov, Igor I.V., Romero, Anntherese A.E., Karki, Menuka, Otero, Isaiah, Hayden, Kathryn, Evdokimov, Nikolai N.M., Banuls, Laetitia Moreno Y, Rastogi, Shiva S.K., Smith, Ross W.R., Lu, Shi-Long, Kiss, Robert, Shuster, Charles C.B., Hamel, Ernest, Betancourt, Tania, Rogelj, Snezna, and Kornienko, Alexander
- Abstract
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 [3H]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. © 2013 American Chemical Society., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2013