Toxicity, Half-Life and Antitumor Activity of Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as Novel Antimitotic CYP1A1-Targeted Prodrugs in Female Mouse Models
Bibliographic record
Abstract
Background/Objectives: Chemoresistance of breast cancers (BCs) is a major impediment to current chemotherapeutics that urges the development of new drugs and new therapeutic approaches. To that end, phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) were recently prepared to fulfill some of the unmet needs with classic chemotherapeutics. PAIB-SOs are prodrugs bioactivated into potent antimitotics by the cytochrome P450 1A1 (CYP1A1), which is a frequent enzyme in resistant BC cells, but mostly missing in normal cells. Our screening program studies of PAIB-SO chemolibraries selected three prototypical PAIB-SOs as antimitotic prodrugs amenable for studies using BC animal models. Methods: Healthy female CD1® IGS mice were treated with three prototypical PAIB-SOs, namely CEU-835, -934, and -938, for the determination of their toxicity and half-lives. Moreover, MCF7 tumor-bearing CD1-Foxn1nu Nude female mice were treated with the three prototypical PAIB-SOs for the determination of their antitumor activity. Results: Herein, we show that multi-intravenous administrations of CEU-835, -934, and -938 at their maximal solubilities are well tolerated in healthy female CD1® IGS mice, as depicted by the evaluation of distress behaviors, organ necropsy, total blood cell count, and histology. Moreover, the half-life of CEU-835, -934, and -938 administered intravenously in healthy CD1® IGS female mice were 8.1, 23.2, and 21.5 h, respectively. Finally, their intravenous administrations of CEU-934 and -938 decreased MCF7 tumor growth as efficiently as paclitaxel in MCF7 tumor-bearing CD1-Foxn1nu Nude mouse model. Conclusions: overall, our study demonstrated for the first time that pentyl-bearing PAIB-SOs are new CYP1A1-dependent prodrugs efficiently decrease breast cancer tumor growth, and show no side effects at their pharmacological concentration in mouse models.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
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".