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

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