Novel Cytocidal Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl) Benzenesulfonates and Benzenesulfonamides with Affinity to the Colchicine-Binding Site: Is the Phenyl 2-Imidazolidinone Moiety a New Haptophore for the Design of New Antimitotics?
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
Phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and phenyl 4-(2-oxoimidazolidin- 1-yl)benzenesulfonamides (PIB-SAs) are new, potent combretastatin A-4 (CA-4) analogs designed on the basis of their common phenyl 2-imidazolidone moiety. This phenyl 2-imidazolidone group is a bioisosteric equivalent of the trimethoxyphenyl group also found in colchicine, podophyllotoxin and several other ligands of the colchicine-binding site (C-BS). In this study, we investigate the interactions involved in the binding of PIB-SO and PIB-SA into the C-BS. We describe three distinct pockets (I, II, and III) as key structural elements involved in the interactions between the C-BS and PIB-SOs as well as PIB-SAs. We show that PIB-SOs and PIB-SAs adopt 4 and 3 distinct binding conformations, respectively, within the C-BS. The binding conformations I and IV are common to most PIB-SOs and PIB-SAs exhibiting high affinity for the C-BS and high cytocidal potency. In addition, binding conformation I is the main conformation adopted by PIB-SOs, PIB-SAs, T138067, ABT-751, colchicine and CA-4. We also observe that the sulfonate and the sulfonamide moieties of PIB-SOs and PIB-SAs are bioisosteric equivalents. Interestingly, we further find that a large portion of the phenyl 2-imidazolidinone moiety in these analogs does not bind to pocket I unlike the trimethoxyphenyl moiety found in several antimicrotubule agents such as colchicine, CA-4 and podophyllotoxin, suggesting that the phenyl 2-imidazolidinone group may represent a new haptophoric moiety useful for the design of new C-BS inhibitors mimicking the tropolone and the methoxylated phenolic moieties of colchicine and CA-4, 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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 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 it