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. 2013 Sep 12;56(17):6886-900. doi: 10.1021/jm400711t.
Liliya V Frolova  1 ,  Igor V Magedov ,  Anntherese E Romero ,  Menuka Karki ,  Isaiah Otero ,  Kathryn Hayden ,  Nikolai M Evdokimov ,  Laetitia Moreno Y Banuls ,  Shiva K Rastogi ,  W Ross Smith ,  Shi-Long Lu ,  Robert Kiss ,  Charles B Shuster ,  Ernest Hamel ,  Tania Betancourt ,  Snezna Rogelj ,  Alexander Kornienko
Affiliations
  • 1. Department of Chemistry and ‡Department of Biology, New Mexico Institute of Mining and Technology , Socorro, New Mexico 87801, United States.
PMID: 23927793 DOI: 10.1021/jm400711t
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 [(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.