Abstract
Thymidylate synthase (TS) is a hot target for tumor chemotherapy, and its inhibitors are an essential direction for anti-tumor drug research. To our knowledge, currently, there are no reported thymidylate synthase inhibitors that could inhibit cancer cell migration. Therefore, for optimal therapeutic purposes, combines our previous reports and findings, we hope to obtain a multi-effects inhibitor. This study according to the principle of flattening we designed and synthesized 18 of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenyl urea derivatives as multi-effects inhibitors. The biological evaluation results showed that target compounds could significantly inhibit the hTS enzyme, BRaf kinase and EGFR kinase activity in vitro, and most of the compounds had excellent anti-cell viability for six cancer cell lines. Notably, the candidate compound L14e (IC50 = 0.67 μM) had the superior anti-cell viability and safety to A549 and H460 cells compared with pemetrexed. Further studies had shown that L14e could cause G1/S phase arrest then induce intrinsic apoptosis. Transwell, western blot, and tube formation results proved that L14e could inhibit the activation of the EGFR signaling pathway, then ultimately achieve the purpose of inhibiting cancer cell migration and angiogenesis in cancer tissues. Furthermore, in vivo pharmacology evaluations of L14e showed significant antitumor activity in A549 cells xenografts with minimal toxicity. All of these results demonstrated that the L14e has the potential for drug discovery as a multi-effects inhibitor and provides a new reference for clinical treatment of non-small cell lung cancer.
Highlights
Numerous chemotherapeutic drugs harm healthy tissues while treating cancer, and a single targeted drug does not achieve satisfactory therapeutic effects
The compound L4a-L4c was subjected to Curtius rearrangement reaction at 80 °C to obtain compounds L5a-L5c which was reacted with the corresponding substituted aniline (L6d-L6i) to obtain a corresponding substituted nitrophenylurea compound (L7d-L7i, L8d-L8i, and L9d-L9i)
When purifying the target compound, we found that the solubility of the compound at a pH of 8.0 to 9.0 is from 0.1 to 0.5 g/mL
Summary
Numerous chemotherapeutic drugs harm healthy tissues while treating cancer, and a single targeted drug does not achieve satisfactory therapeutic effects. We are committed to the development of a multi-effect antitumor drug. Thymidylate synthase (TS) involves in the process of DNA replication and repair[1,2,3,4], is a critical wellrecognized target for anticancer agents. The regulatory role of TS may be implicated in the synthesis of key proteins that regulate the apoptotic process[5]. We reported a series of TS inhibitors based on N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)benzoyl hydrazide skeleton with IC50 values around 10–20 μM. Compound 10l, the most potent one in the series, had excellent anti-proliferation ability
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