The natural steroidal alkaloid cyclopamine has been identified as the first inhibitor of
the Hedgehog (Hh) signaling pathway, which is implicated in embryonic development and tumorigenesis,
as well as is hyperactivated in cancer stem cells (CSCs). The list of Hh-dependent
tumors is steadily growing, and it has been estimated that about 25% of all cancer deaths show
signs of aberrant Hh pathway activation. Notably, cyclopamine has been found to exert anticancer
activity against several types of human cancer and to inhibit CSCs proliferation, thus highlighting
the druggability of the Hh pathway and paving new opportunities in anticancer drug discovery.
The aim of the present work is to review the main synthetic strategies to cyclopamine and its derivatives, with particular emphasis on the
challenging chemical modifications aimed at improving the biological activity of the molecule.
Keywords: Cyclopamine, hedgehog pathway, anticancer, organic synthesis, C-nor-D-homosteroid, Veratrum alkaloids.
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