2. Academic Validation
  3. 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

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

Affiliation

  • 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.

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