Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido) phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity

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 (IC 50 = 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.

Genome-wide Screens Identify Lineage- and Tumor Specific-Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

“…5fluorouracil was introduced in 1957 (Heidelberger et al, 1957), and TS inhibitors are currently approved in treatment of breast, colon and rectum, gastric, gastroesophageal junction, and pancreatic adenocarcinomas as well as nonsquamous, non-small cell lung cancers. Still, studies continue to investigate TS catalysis and attempt to improve the functionality of TS inhibitors (Kholodar et al, 2018;Li et al, 2019).…”

New Natural Eugenol Derivatives as Antiproliferative Agents: Synthesis, Biological Evaluation, and Computational Studies

“…The outcomes of cell cycle and apoptosis studies were found to be in agreement with the reported literature. 34,35 In Silico Physicochemical and Pharmacokinetics Studies. The development of new drugs has been a costly, risky and challenging venture with a low victory success rate.…”

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“…Thymidylate synthase is involved in the process of DNA replication and repair, and controls the synthesis of apoptosis‐related proteins. [ 98 ] Therefore, thymidylate synthase is considered as an important target of anticancer drugs. Based on this principle, many famous pyrimidine‐based NADs have been synthesized, including 5‐fluorouracil and 5‐(trifluoromethyl)‐uracil (Figure 8).…”