Development of CPA‐Catalyzed β‐Selective Reductive Amination of Cardenolides for the Synthesis and Biological Evaluation of Hydrolytically Stable Analogs
Bibliographic record
Abstract
Abstract 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 15 g 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 , 13 g , 15a , and 15 g demonstrated that these four analogs reduced steady‐state ATP1A1 levels in T98G cells in the 12–96 nM range. Interestingly, only the oleandrin analog 15 g lowered also steady‐state levels of the cellular prion protein (PrP C ), the main therapeutic target for the treatment of prion diseases.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".