Synthesis and biological evaluation of new thiazolyl-urea derivatives as potential dual C-RAF/FLT3 inhibitors

• Published in: Medicinal chemistry research Vol. 31; no. 11; pp. 1862 - 1874
• Main Authors: Zhang, Zhi-Hua, Zeng, Bi-Fan, Song, Zhe-Xue, Yang, Ying-Yu, Zhang, Kai-yun, Du, Xue, Zhang, Lin-lin, Cai, Dong
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2022; Springer Nature B.V
• Subjects: Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cell cycle; Cell proliferation; Hepatocellular carcinoma; Inorganic Chemistry; Kinases; Medicinal Chemistry; Pharmacology/Toxicology; Review Article; Ureas; 4-phenylthiazol-2-amine; Cell cycle analysis; Dual C-RAF/FLT3 inhibitors; Cell migration; Anticancer activity; Cell apoptosis
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-022-02971-2

Based on a structure-activity relationship of compounds such as Sorafenib and Quizartinib, a series of thiazol-urea derivatives containing hydrophilic side moiety were designed and synthesized, aiming to improve the druggability of target compounds. Among them, compound 6h exhibited the best anti-hepatocellular carcinoma activity, especially against HepG2 cells with an IC 50 of 5.62 μM. In addition, compound 6h was able to suppress the formation of HepG2 colonies. Mechanism studies revealed that compound 6h effectively inhibited C-RAF/FLT3 kinases. Furthermore, compound 6h was able to inhibit the rapid proliferation, and exerted marked migration inhibitory effects on HepG2 cells. Moreover, compound 6h induced cell cycle arrest in G2/M phase and led to cell apoptosis. Besides, ADMET properties prediction showed that compound 6h had more aqueous solubility than Sorafenib. Collectively, these results suggested that compound 6h represents a novel C-RAF/FLT3 inhibitor deserving further investigation.