Synthesis and biological evaluation of novel N-phenyl ureidobenzenesulfonate derivatives as potential anticancer agents. Part 2. Modulation of the ring B

Abstract

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.

Preparation, characterisation and biological evaluation of new N-phenyl amidobenzenesulfonates and N-phenyl ureidobenzenesulfonates inducing DNA double-strand breaks. Part 3. Modulation of ring A

“…In some cases, the last nucleophilic addition requires heating under pressure in the presence or absence of microwaves. Topotecan, SFOM-0106, SFOM-0107 and SFOM-0046 were used as reference controls [2,4]. Antiproliferative activities are shown in Table 1 and represent the concentration of the drug inhibiting cell growth by 50% (IC50).…”

“…To that end, we developed a new family of anticancer agents named N-phenyl ureidobenzenesulfonates (PUB-SOs, Fig. 1A) [2][3][4]. The molecular structure of PUB-SOs is constituted of 2 aromatic rings (rings A and B) and a sulfonate group bridging the two aromatic rings.…”

“…Hitherto, we found that PUB-SOs bearing 2-alkyls, 2-halogens, 2-nitro or 4-hydroxyl groups substituting ring B and an ethylurea, a 2-chloroethylurea or a 3-chloropropylurea groups substituting position 4 of ring A lead to derivatives exhibiting antiproliferative activity at the micromolar level, blocking the cell cycle progression in S-phase and inducing γH2AX formation [2][3][4]. other PUB-SOs showed potent antitumoral activity on human HT-1080 fibrosarcoma tumors grafted onto the chorioallantoic membrane of chick embryos with low toxicity toward the embryos showing that PUB-SOs are a promising family of anticancer agents [2,11].…”

“…In addition, our previous SAR studies involving ring B modifications using a 2-chloroethylurea moiety at position 4 on ring A showed that PUB-SOs bearing a 2-isopropyl or a 2-iodo groups on ring B referred to as 2-isopropylphenyl 4-(3-(2-chloroethyl)ureido)benzenesulfonate (SFOM-0107) and 2-iodophenyl 4-(3-(2-chloroethyl)ureido)benzenesulfonate (SFOM-0106, Fig. 1C), respectively are the most potent antiproliferative PUB-SOs prepared so far and exhibit the highest blocking activity of the cell cycle progression in S-phase [4].…”

Investigation of the DNA damage response to SFOM-0046, a new small-molecule drug inducing DNA double-strand breaks

“…We recently uncovered a new class of compounds designated as N -phenyl ureidobenzenesulfonates (PUB-SOs, Fig. 1 ) that exhibited antiproliferative activity in the micromolar range on several human tumour cell lines notably M21 skin melanoma, estrogen-dependent MCF-7 breast adenocarcinoma and HT29 colon adenocarcinoma 21 22 . PUB-SOs blocked Jurkat cell cycle progression in S-phase and induced the formation of γ-H2AX in M21 cells, indicating that these new agents led to DNA replication stress.…”