Research Progress of Diphenyl Urea Derivatives as Anticancer Agents and Synthetic Methodologies

The malignant neoplasm, which is recognized as cancer, is a serious threat to human health and frequently-occurring disease. Diphenylurea, an important link structure in the design of active substance for treating cancer due to its near-perfect binding with certain acceptors, has demonstrated many activities against several human cancer cell lines. Various novel compounds with diphenyl urea as anticancer agents were constructed with the successful development of sorafenib. Diphenylurea is utilized to treat cancer by inhibiting cell signaling transduction, such as RAS-RAF-MEK-ERK signaling pathway and PI3K-Akt-mTOR pathway. In addition, this structure inhibits tumor cell growth by inhibiting receptor tyrosine kinases multiply, such as Vascular Endothelial Growth Factor Receptors (VEGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), Epidermal Growth Factor Receptors (EGFRs). It regulates the pH value in cells by inhibiting CAIX/XII and to achieve cancer therapeutic effect. Besides, the diphenyl urea structure is applied to the synthesis of reagents like Aurora kinases inhibitors and HDAC inhibitors that affect cell division and differentiation to treat cancer. To reach the goal of treating tumor, this structure is also used as a DNA-directed alkylating agent by affecting the expression of genes. An application of the most representative diphenyl urea derivatives as antitumor agents is summarized in this review, focusing on their mechanisms bound to the targets. Meanwhile, the progress of researches on methods of synthesizing diphenyl urea derivatives is provided.