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

Abstract

We developed synthetic chemistry to access the marine alkaloid rigidins and over forty 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.

Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9‐Epipolygodial against Drug‐Resistant Cancer Cells

“…50 Analysis of these data reveals that polygodial ( 1 ) and most of the synthesized derivatives displayed little activity in this cancer cell line panel, with the exception of 9-epipolygodial ( 2 ). Compound 2 was at least 20 times as potent as polygodial ( 1 ) and did not appear to discriminate between apoptosis resistant and apoptosis-sensitive cells by displaying comparable single digit micromolar potencies in both cell types (Table 1).…”

Synthetic and Biological Studies of Tubulin Targeting C2‐Substituted 7‐Deazahypoxanthines Derived from Marine Alkaloid Rigidins

“…However, despite the earlier reports of promising antiproliferative activity against murine leukemia L1210 cells, 11 the rigidins were found to have very little, if any, activity against cultured human cancer cells. 14 Further synthetic investigations led to the development of approaches allowing for the modification of the 7-deazaxanthine skeleton present in the rigidins to obtain the corresponding 7-deazahypoxanthine ( A ), 7-deazaadenine ( B ) and 7-deazapurine ( C ) frameworks (Figure 1). These studies culminated in the discovery of potent antiproliferative activities associated with the synthesized 7-deazahypoxanthines ( A ) and their ability to disrupt microtubule organization in cancer cells by binding to the colchicine site of β-tubulin.…”

Fungal metabolite ophiobolin A as a promising anti-glioma agent: In vivo evaluation, structure–activity relationship and unique pyrrolylation of primary amines

“…39 Analysis of these data shows that derivatives with the eliminated C5,C21-dicarbonyl functionality, such as compounds 4–8 and 15–18 , have significantly reduced potencies as would be expected due to the critical importance of this moiety for anticancer activity. In contrast, compounds incorporating modifications of the C18,C19-alkene, such as 10 – 14 , have retained a significant portion of the antiproliferative potency.…”