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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
Frolova, L.; Magedov, I.; Romero, A.; Karki, M.; Otero, I.; Hayden, K.; Evdokimov, N.; Banuls, L.M.Y.; Rastogi, S.; Smith, W.; Lu, S.; Kiss, R.; Shuster, C.; Hamel, E.; Betancourt, T.; Rogelj, S.; Kornienko, A. (2013). 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. J. Med. Chem. 56(17): 6886-6900. https://dx.doi.org/10.1021/jm400711t
In: Journal of Medicinal Chemistry. American Chemical Society: Easton. ISSN 0022-2623; e-ISSN 1520-4804, meer
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| Auteurs | | Top |
- Frolova, L.
- Magedov, I.
- Romero, A.
- Karki, M.
- Otero, I.
- Hayden, K.
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- Evdokimov, N.
- Banuls, L.M.Y.
- Rastogi, S.
- Smith, W.
- Lu, S.
- Kiss, R., meer
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- Shuster, C.
- Hamel, E.
- Betancourt, T.
- Rogelj, S.
- Kornienko, A.
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| 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 [H-3]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. |
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