Abstract 4487: Design, synthesis, and biological activity of N-phenyl ureidobenzenesulfonates (PUB-SOs) as new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms
Bibliographic record
Abstract
Abstract Our research group has developed a new family of promising anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs). PUB-SOs are based on a genuinely new molecular scaffold and pharmacophore constituted by two key aromatic moieties linked by a sulfonate bridge. PUB-SOs block the cell cycle progression in the S-phase and cause DNA double-strand breaks as confirmed by the phosphorylation of H2AX. In addition, PUB-SOs exemplified by prototypical PUB-SO referred to as SFOM-0046 activate selectively ATR-Chk1 pathway in all cell lines studied while it does not activate the ATM-Chk2 pathway. Using immunofluorescence, cell cycle analysis and cell survival assays, we showed that the combination of the Chk1 inhibitor 7-hydroxystaurosporine (UCN-01) and SFOM-0046 provide a proof-of concept that the cytotoxicity of PUB-SOs can be synergized by relevant anticancer drugs. Accordingly, we hypothesized that PUB-SOs inhibit proteins or enzymes involved in critical DNA repair/replication mechanisms. In such a context, we designed a new structure-activity relationship study to assess the effects of the nature and position of different substituents on the aromatic ring B. More than 50 new PUB-SO derivatives were prepared so far and they exhibit antiproliferative activity on the low micromolar range on HT-1080 fibrosarcoma, HT-29 colon carcinoma, M21 skin melanoma and MCF7 breast carcinoma. They block also the cell cycle progression in the S-phase. These results show that substituents on ring B can be modulated to optimize both the antiproliferative and as well as biopharmaceutical properties. In conclusion, PUB-SOs are easily synthesized, purified and pharmacomodulated, and they are therefore promising new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms through a genuinely innovative molecular scaffold and pharmacophore. Citation Format: Sébastien Fortin, Hanane Moussa, Mathieu Gagné-Boulet, Jacques Lacroix, Marie-France Côté, Denis Velic, Joris Pauty, Jean-Yves Masson. Design, synthesis, and biological activity of N-phenyl ureidobenzenesulfonates (PUB-SOs) as new and innovative small-molecule drugs inhibiting proteins involved in DNA repair/replication mechanisms. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4487. doi:10.1158/1538-7445.AM2015-4487
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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 | 0.000 | 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".