par 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
Référence Journal of medicinal chemistry, 56, 17, page (6886-6900)
Publication Publié, 2013-09
Référence Journal of medicinal chemistry, 56, 17, page (6886-6900)
Publication Publié, 2013-09
Article révisé par les pairs
Résumé : | 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. |