Silicon-Tethered Intramolecular [5+2] Oxidopyrylium-Based Cycloaddition and Reductive Cleavage of Ether Bridge: Synthetic Studies Toward Arteminolides

摘要

Arteminolides A-D (1-4), natural triterpene lactones, were isolated from the leaves of Artemisia sylvatica Maxim and have been reported to be strong inhibitiors of farnesyl-trnasferase (FTase) targeting members of the Ras super-family of small GFTP-binding proteins critical to cell cycle progression. Thus, arteminolides have displayed the tumor cell growth inhibition in a dose-dependent manner. In addition, arteminolide A (1) exhibited selective inhibition of recombinant rat FTase with no significant inhibition of rat squalene synthase or geranylgeranyltransferase (GGTase), and arteminolide C (3) blocked in vivo growth of human colon and lung tumor xenograft without the loss of body weight in nude mice. As well as the biological profile their structural complexity with the rigid ring skeleton could facilitate the study on the structure-activity relationships (SARs) with three dimensional information, which can direct new FTase inhibitor with high therapeutic value. Despite their favorable biological profile and intriguing structural complexity the success in the synthesis of arteminolides has not been reported since their first isolation in 1998.