Solid‐phase synthesis of amanitin derivatives and preliminary evaluation of cellular uptake and toxicity
Bibliographic record
Abstract
Abstract The study of transcriptional arrest is of great importance and can provide insight into the cellular response to various toxins, most notably chemotherapeutics. Therefore, specific inhibitors of RNA Polymerase II (RNAP II) could prove to be extremely useful. Given that α‐amanitin is one of the most potent and selective inhibitors of RNAP II, we prepared two amanitin derivatives on solid phase as a proof of principle towards the development of a One‐Bead‐One‐Compound (OBOC) amanitin chemical library. The amatoxin family comprises several related toxic peptides that are characterized by a defined rigid bicyclic structure based on a head‐to‐tail cyclized octapeptide, with a transannular tryptathionine crosslink. The latter is prepared via the Savige‐Fontana tryptathionylation of the oxidized tryptophan derivative 3a‐hydroxypyrrolo[2,3‐b]indoline in neat TFA. We synthesized a new fluorescently labelled S‐deoxo‐[Asn1‐TEG‐DEAC, Ile3]‐amaninamide (Ile3‐Ama) and studied its ability to be taken up by CHO cells and to stain the nucleus, the site of transcriptionally active DNA. Towards the solid phase synthesis of an amanitin‐inspired library, we synthesized a linker that is stable both in TFA, used to promote the tryptathionine crosslink, and base used for Fmoc‐deprotection. The linker allowed the full synthesis of an amanitin derivative on solid phase, including tryptathionylation and macrolactamization.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".