Structure–activity relationship of caffeic acid phenethyl ester analogs as new 5‐lipoxygenase inhibitors
Why this work is in the frame
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Bibliographic record
Abstract
Leukotrienes ( LT s) are a class of lipid mediators implicated in numerous inflammatory disorders. Caffeic acid phenethyl ester ( CAPE ) possesses potent anti‐ LT s activity through the inhibition of 5‐lipoxygenase (5‐ LO ), the key enzyme in the biosynthesis of LT s. In this study, we describe the design and synthesis of CAPE analogs as radical scavengers and 5‐ LO inhibitors. Caffeic esters bearing propargyl and allyl linkers between the caffeoyl and aryl moieties ( 4a–i and 5a–i , respectively) were synthesized by Sonogashira and Heck cross‐coupling reactions to probe the effects of flexibility and aryl substitution on 5‐ LO inhibition. Caffeoyl alcohol and ethers ( 6 , 7a–b ) as well as caffeoyl aldehyde and ketones ( 8a–e ) were synthesized to elucidate the importance of the ester linkage for inhibitory activity. All tested compounds proved to be good radical scavengers ( IC 50 of 10–30 μ m ). After preliminary anti‐ LT s activity screening in HEK 293 cell models, 5‐ LO inhibition potential of selected compounds was determined in human polymorphonuclear leukocytes ( PMNL ). Most screened compounds outperformed CAPE 3 in concentration‐dependent assays on PMNL , with ester dimers 4i and 5i along with caffeoyl ethers 7a–b being roughly eight‐, seven‐, and 16‐fold more potent than Zileuton, with IC 50 values of 0.36, 0.43, and 0.18 μ m , respectively.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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 | 0.000 |
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 it