A novel strategy to bind pyrimidine sulfonamide derivatives with odd even chains: exploration of their design, synthesis and biological activity evaluation.

Based on the hybridization strategy of dominant fragments, a series of pyrimidine sulfonamide (PS) derivatives were obtained by combining the pharmacophore fragments (sulfonamide group and pyrimidine group) with different biological activities, and evaluated as a new type of anticancer drug. The compounds were evaluated for in vitro cytotoxicity against four human cancer cell lines (HeLa, HCT-116, A-549 and HepG2) and the normal human cell line L02. Compared with the anti-cancer drug 5-fluorouracil (5-FU), the antiproliferative activity of compound PS14 was close to 5-FU and it has good antitumor activity. The IC50 values were 15.13 ± 2.20, 19.87 ± 2.01, 12.64 ± 3.22, 22.20 ± 1.34 and 102.46 ± 2.27 μM, respectively. The structure activity relationship was analyzed. The antitumor activity of the compound tended to increase. When the substituents of the branch chain of sulfonamides were odd. In addition, the oil-water partition coefficient was also investigated. The logP value of PS14 was between 0 and 3, indicating that PS14 was a compound with good lipophilic property, poor water solubility and easy to be absorbed and transported through cell membrane. The anti-cancer mechanism was further studied by flow cytometry. After PS14 treated HeLa, HCT-116, A-549 and HepG2, the percentage of apoptotic cells was 45.30%, 28.2%, 31.00% and 35.20%, respectively, which was higher than that of the control 5-FU. The results of cell cycle showed that PRD2 mainly blocked the cell cycle in the S phase, thereby inhibiting cell proliferation. Furthermore, molecular docking analyzed possible interactions between the compound and the PI3Kα active site, this compound has good binding with PI3Kα. Overall, this study laid the groundwork for the development and structural modification of new pyrimidine sulfonamide drugs, and PS14 could be further developed into a cancer treatment drug.