Novel Oxadiazole‐Based Bioisostere of Caffeic Acid Phenethyl Ester: Synthesis, Anticancer Activity, and Inhibition of Lipoxygenase Product Biosynthesis
Bibliographic record
Abstract
ABSTRACT Caffeic acid phenethyl ester ( 1 ), a honeybee propolis component, possesses many bioactive properties, making it a useful scaffold for drug research. Further, CAPE ( 1 ) is a more effective inhibitor of the biosynthesis of 5‐lipoxygenase (5‐LO) products compared to Zileuton, the only clinically‐approved direct 5‐LO inhibitor. However, CAPE ( 1 ) suffers from a poor metabolic profile, being rapidly metabolized to caffeic acid (CA). In this study, we synthesized and performed several biological assays on a new bioisostere of CAPE ( 1 ) possessing a 1,2,4‐oxadiazole ring. The new bioisostere (OB‐CAPE ( 5 )) has a similar antiproliferative effect to CAPE ( 1 ) on NCI‐60 cancer cell lines and maintains the activity of CAPE ( 1 ) as an inhibitor of the biosynthesis of 5‐, 12‐ and 15‐LO products and as an iron chelator. In human polymorphonuclear leukocytes, OB‐CAPE ( 5 ) inhibits the biosynthesis of 5‐LO products with an IC 50 of 0.93 µM compared to 1.0 µM for CAPE ( 1 ). Both compounds have similar antioxidant activity, with IC 50 values of 1.2 µM for OB‐CAPE ( 5 ) and 1.1 µM for CAPE ( 1 ). The new hydrogen bond predicted for the oxadiazole ring and the GLN363 amino acid in the 5‐LO active site may explain the small improvement in the affinity of OB‐CAPE ( 5 ) for the protein compared to CAPE ( 1 ). Finally, stability studies in human plasma reveal that OB‐CAPE ( 5 ) is 25% more stable than CAPE ( 1 ). Therefore, the increase in stability associated with the replacement of the ester function with its bioisostere, while maintaining the anti‐inflammatory and anticancer properties of CAPE ( 1 ), suggests that OB‐CAPE ( 5 ) may be a comparable yet more stable candidate for in vivo studies in disease models.
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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 | 0.002 | 0.000 |
| 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) | 0.000 | 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".