Podophyllotoxin is a lignan natural product that has been pursued as a lead compound for therapeutic development. It is a World Health Organization essential medicine and its derivatives, etoposide, teniposide, and etopophos, have been advanced to clinical anticancer drugs. Podophyllotoxin targets the colchicine-binding site of tubulin, inhibiting the polymerization to microtubules causing cell death in a large variety of cancer cell lines with an average IC<sub>50</sub>value of 52.7 nM. However, its further development has been hindered by significant off-target toxicity. While extensive SAR has been conducted, derivatizations have largely focused on alcohol appendages or sacrificing the D-ring lactone as a handle to introduce novel functionality. Herein we report on the synthesis and biological evaluation of novel medium-ring analogues of podophyllotoxin, which offer altered three-dimensional architectures that mimic that of the native ligand colchicine. The key transformation engages the benzylic alcohol in a hypervalent iodine-mediated oxidative ring expansion developed in our laboratory. The newly formed oxepane ring possess an acetal center that is then further functionalized with sterically and electronically diverse motifs, leading to the synthesis of 18 unique derivatives, all available within three steps from the natural product. Biological evaluation of the analogues has been paired with computational modeling to guide the continued development of improved compounds.

Late stage derivation of podophyllotoxin using oxidative ring expansion

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.