Synthesis and evaluation of carbagalactosyl 1,2-aziridines and -epoxides as glycosidase inhibitors
Bibliographic record
Abstract
The natural product cyclophellitol is a cyclitol epoxide that mimics a β-glucoside and functions as a mechanism-based inhibitor for retaining β-glucosidases by forming a stable covalent intermediate with the enzyme's catalytic nucleophile. The epoxide is located across the carbons equivalent to C1 and O5 of glucose, and multiple congeners have been synthesised, as well as the corresponding aziridines, and shown to inactivate their cognate glycosidases. In a quest for a potent covalent inactivator of an α-galactosaminidase that is used in the conversion of A type blood to O type through modification of the antigen, we synthesised the galacto-configured 1,2-α-aziridine in which the aziridine ring is located across the carbons equivalent to C1 and C2. While neither this nor the corresponding epoxide inactivated our enzyme or any of the α-galactosidases tested, the β-configured analogues were shown by mass spectrometry to function as covalent inactivators of several β-glycosidases and their inactivation behaviour characterised kinetically. Molecular modeling indicates that 1,2-α-aziridines adopt an unfavorable conformation in solution, preventing binding to the enzyme active site. The synthesis of these compounds and their activities as inhibitors and inactivators of glycosidases of different families will direct future attempts to develop inactivators beyond those of the more common cyclophellitol class.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".