DNA double strand-breaks (DSBs) are the most deleterious lesions that can affect the genome of living beings and are lethal if not quickly and properly repaired. Recently, we discovered a new family of anticancer agents designated as N-phenyl ureidobenzenesulfonates (PUB-SOs) that are blocking the cells cycle progression in S-phase and inducing DNA DSBs. Previously, we have studied the effect of several modifications on the molecular scaffold of PUB-SOs on their cytocidal properties. However, the effect of the nature and the position of substituents on the aromatic ring B is still poorly studied. In this study, we report the preparation and the biological evaluation of 45 new PUB-SO derivatives substituted by alkyl, alkoxy, halogen and nitro groups at different positions on the aromatic ring B. All PUB-SOs were active in the submicromolar to low micromolar range (0.24-20 μM). The cell cycle progression analysis showed that PUB-SOs substituted at position 2 by alkyl, halogen or nitro groups or substituted at position 4 by a hydroxyl group arrest the cell cycle progression in S-phase. Interestingly, all others PUB-SOs substituted at positions 3 and 4 arrested the cell cycle in G2/M-phase. PUB-SOs arresting the cell cycle progression in S-phase also induced the phosphorylation of H2AX (γH2AX) which is indicating the generation of DNA DSBs. We evidenced that few modifications on the ring B of PUB-SOs scaffold lead to cytocidal derivatives arresting the cell cycle in S-phase and inducing γH2AX and DSBs. In addition, this study shows that these new anticancer agents are promising and could be used as alternative to circumvent some of the biopharmaceutical complications that might be encountered during the development of PUB-SOs.

Dietary omega-3 fatty acids (ω3), particularly long-chain ω3 (LCω3), have protective effects against prostate cancer (PCa) in experimental studies. Observational studies are conflicting, possibly because of the biomarker used. This study aimed at evaluating associations between grade reclassification and ω3 levels assessed in prostatic tissue, red blood cells (RBC), and diet. We conducted a validation cross-sectional study nested within a phase II clinical trial. We identified 157 men diagnosed with low-risk PCa who underwent a first active surveillance repeat prostate biopsy session. Fatty acid (FA) intake was assessed using a food frequency questionnaire and their levels measured in prostate tissue and RBC. Associations were evaluated using logistic regression. At first repeat biopsy session, 39 (25%) men had high-grade PCa (grade group ≥2). We found that high LCω3-eicosapentaenoic acid (EPA) level in prostate tissue (odds ratio (OR) 0.25; 95% (confidence interval (CI) 0.08–0.79; p-trend = 0.03) was associated with lower odds of high-grade PCa. Similar results were observed for LCω3 dietary intake (OR 0.30; 95% CI 0.11-0.83; p-trend = 0.02) but no association for RBC. LCω3-EPA levels in the target prostate tissue are inversely associated with high-grade PCa in men with low-risk PCa, supporting that prostate tissue FA, but not RBC FA, is a reliable biomarker of PCa risk.

Prostate cancer (PCa) and associated treatments incur symptoms that may impact patients’ quality of life. Studies have shown beneficial relationships between diet, especially omega-3 fatty acids, and these symptoms. Unfortunately, only few data describing the relationship between long-chain omega-3 fatty acids (LCn3) and PCa-related symptoms in patients are available. The purpose of this study was to evaluate the effects of LCn3 supplementation on PCa-specific quality of life in 130 men treated by radical prostatectomy. Men were randomized to receive a daily dose of either 3.75 g of fish oil or a placebo starting 7 weeks before surgery and for up to one-year post-surgery. Quality of life was assessed using the validated EPIC-26 and IPSS questionnaires at randomization, at surgery, and every 3 months following surgery. Between-group differences were assessed using linear mixed models. Intention-to-treat analyses showed no significant difference between the two groups. However, at 12-month follow-up, per-protocol analyses showed a significantly greater increase in the urinary irritation function score (better urinary function) (MD = 5.5, p = 0.03) for the LCn3 group compared to placebo. These results suggest that LCn3 supplementation may improve the urinary irritation function in men with PCa treated by radical prostatectomy and support to conduct of larger-scale studies.

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