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
Year: 2013
Type: article
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.
Source: Journal of Medicinal Chemistry
DOI: 10.1021/jm400711t
Authors: Liliya V. Frolova, 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
Institutions: New Mexico Institute of Mining and Technology, New Mexico State University, Université Libre de Bruxelles, Frederick National Laboratory for Cancer Research, National Cancer Institute, University of Colorado Anschutz, Texas State University, University of Colorado Denver, National Institutes of Health
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G1698359904, The Role of PI3K Pathway in Head and Neck Cancer Invasion and Metastasis, New Mexico IDeA Networks of Biomedical Research Excellence (INBRE) [P20], Heterocyclic Analogues of Podophyllotoxin Accessible by a One-Step Multicomponent, New Mexico IDeA Networks of Biomedical Research Excellence (INBRE)
OpenAlex ID: W1999706763