Preparation of Antiproliferative Terpene-Alkaloid Hybrids by Free Radical-Mediated Modification of ent-Kauranic Derivatives

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C-C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.

Automated summary

A convenient molecular editing strategy based on radical mediated C-C bond formation has been developed for modification of available ent-kauranic natural scaffolds. The study shows that this strategy can lead to the synthesis of extended diterpenes with broad structural diversity and artificial diterpene-alkaloid hybrids, some of which exhibit significant cytotoxicity and promising selectivity indexes. These findings provide a solid foundation for further research on the synthesis of derivatives based on available natural product templates.