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.
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.
Department of Chemistry and ‡Department of Biology, New Mexico Institute of Mining and Technology , Socorro, New Mexico 87801, United States.
Liliya V
LV
Frolova
Igor V
IV
Magedov
Anntherese E
AE
Romero
Menuka
M
Karki
Isaiah
I
Otero
Kathryn
K
Hayden
Nikolai M
NM
Evdokimov
Laetitia Moreno Y
LM
Banuls
Shiva K
SK
Rastogi
W Ross
WR
Smith
Shi-Long
SL
Lu
Robert
R
Kiss
Charles B
CB
Shuster
Ernest
E
Hamel
Tania
T
Betancourt
Snezna
S
Rogelj
Alexander
A
Kornienko
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D003078:Colchicine / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects*
D000470:Alkaloids; D001688:Biological Products; D014404:Tubulin; D003078:Colchicine