Development of CPA-Catalyzed β-Selective Reductive Amination of Cardenolides for the Synthesis and Biological Evaluation of Hydrolytically Stable Analogs.

This article describes the development of novel, hydrolytically stable cardiotonic steroid analogs featuring a 3β-amine moiety instead of the commonly found 3β-carbohydrates such as oleandrose. To establish the desired 3β-configuration stereoselectively, a new method based on chiral phosphoric acid-controlled diastereoselective reductive amination with Hantzsch esters was developed. This method utilizes readily available unsubstituted (S)-BINOL-based hydrogen phosphate as the catalyst, enabling the synthesis of 13 different 5β-androsterone and digitoxigenin analogs with up to 36:1 β:α diastereoselectivity. Additionally, this strategy was applied to generate two novel oleandrigenin analogs 15a and 15g in 3 steps from readily available gitoxigenin. The synthetic analogs were subjected to the NCI-60 human tumor cell lines screen, and several different digitoxigenin derivatives with tumor cell growth inhibitory power in submicromolar range were identified. The subsequent in vitro evaluation of digitoxigenin and oleandrin derivatives 13a, 13g, 15a, and 15g demonstrated that these four analogs reduced steady-state ATP1A1 levels in T98G cells in the 12-96 nM range. Interestingly, only the oleandrin analog 15g lowered also steady-state levels of the cellular prion protein (PrP), the main therapeutic target for the treatment of prion diseases.