How Drug Photodegradation Studies Led to the Promise of New Therapies and Some Fundamental Carbanion Reaction Dynamics along the Way
Bibliographic record
Abstract
The photodegradation of nonsteroidal anti-inflammatory drugs (NSAIDs), a class of medications that includes aspirin and ibuprofen, has generated considerable interest since the 1990s, largely because of the phototoxic and photoallergic effects that frequently accompany their therapeutic use. Among NSAIDs, ketoprofen, which contains a benzophenone chromophore, has been extensively studied, reflecting both its notorious adverse effects and the fascination that photochemists have with benzophenone. The photochemistry of ketoprofen involves the intermediacy of an easily detectable carbanion with a remarkable lifetime of 200 ns in water; its life expectancy can in fact be extended to minutes under carefully controlled anhydrous conditions. Over the past decade, we have used some key properties of the ketoprofen carbanion to conduct mechanistic studies on carbanions under various conditions. In particular, its ease of photogeneration provides the temporal control required for kinetic studies, which, combined with its long lifetime and readily detectable visible absorption, have enabled extensive laser flash photolysis work. These studies have led to an intimate understanding of the reaction dynamics for carbanions in solution, including the determination of absolute rate constants for protonation, S(N)2, and elimination reactions. Together they provide excellent exemplars of reactivity patterns that today are part of all introductory curricula in organic chemistry and illustrate the fundamentals of nucleophilic substitution paradigms. More recently, we have begun to exploit the photochemistry of ketoprofenate and have developed the ketoprofenate photocage, a valuable tool for the photocontrolled cleavage of protecting groups and concomitant drug release. The photorelease has been illustrated with ibuprofen, among many other molecules. These photocages have been further improved with the use of the xanthone chromophore; the goal is the release of antiviral agents taking advantage of the improved UVA absorption of xanthone (xanthonate photocages). In this Account, we survey our work of the past few years on the photochemistry of ketoprofen and related chromophores. Beginning with studies on the phototoxicity of ketoprofen, we have made the journey to new prodrug candidates, unraveling mechanistic elements of aroyl-substituted benzyl carbanions along the way.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.004 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.002 | 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".