Replacement of the lactone moiety on podophyllotoxin and steganacin analogues with a 1,5-disubstituted 1,2,3-triazole via ruthenium-catalyzed click chemistry.
2007
Abstract—Steganacin and podophyllotoxin are two naturally occurring lignans first isolated from plant sources, which share thecapability to disrupt tubulin assembly. Although not strictly essential for its activity, the lactone ring on both structures representsAchilles’ heel, as it is a potential site of metabolic degradation and epimerization on its C2 carbon brings about a significant loss inpotency. In the present manuscript, we have used the ruthenium-catalyzed [3+2] azide–alkyne cycloaddition, a click-chemistry reac-tion, to replace the lactone ring with a 1,5-disubstituted triazole in few synthetic steps. The compounds were cytotoxic, although to alesser degree compared to podophyllotoxin, while retaining antitubulin activity. The present structures might therefore representa good platform for the fast generation of metabolically stable compounds with few stereogenic centers that might be of value froma medicinal chemistry point of view. 2007 Elsevier Ltd. All rights reserved. 1. Introduction( )-Steganacin (1) and ( )-podophyllotoxin (2)(Fig. 1)are two naturally occurring lignans first isolated fromplant sources.
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