Garuti Laura, Roberti Marinella, Bottegoni Giovanni, Ferraro Mariarosaria
Department of Pharmacy and Biotechnology, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.
Curr Med Chem. 2016;23(15):1528-48. doi: 10.2174/0929867323666160411142532.
The diaryl urea is an important fragment/pharmacophore in constructing anticancer molecules due to its near-perfect binding with certain acceptors. The urea NH moiety is a favorable hydrogen bond donor, while the urea oxygen atom is regarded as an excellent acceptor. Many novel compounds have been synthesized and evaluated for their antitumor activity with the successful development of sorafenib. Moreover, this structure is used to link alkylating pharmacophores with high affinity DNA binders. In addition, the diaryl urea is present in several kinase inhibitors, such as RAF, KDR and Aurora kinases. Above all, this moiety is used in the type II inhibitors: it usually forms one or two hydrogen bonds with a conserved glutamic acid and one with the backbone amide of the aspartic acid in the DFG motif. In addition, some diaryl urea derivatives act as Hedgehog (Hh) ligands, binding and inhibiting proteins involved in the homonymous Hh signaling pathway. In this review we provide some of the methodologies adopted for the synthesis of diaryl ureas and a description of the most representative antitumor agents bearing the diaryl urea moiety, focusing on their mechanisms bound to the receptors and structure-activity relationships (SAR). An increased knowledge of these derivatives could prompt the search to find new and more potent compounds.
二芳基脲由于其与某些受体近乎完美的结合，是构建抗癌分子的重要片段/药效基团。脲基NH部分是良好的氢键供体，而脲氧原子被视为出色的受体。随着索拉非尼的成功研发，已经合成并评估了许多新型化合物的抗肿瘤活性。此外，该结构用于连接具有高亲和力DNA结合剂的烷基化药效基团。此外，二芳基脲存在于几种激酶抑制剂中，如RAF、KDR和Aurora激酶。最重要的是，该部分用于II型抑制剂：它通常与保守的谷氨酸形成一个或两个氢键，并与DFG基序中天冬氨酸的主链酰胺形成一个氢键。此外，一些二芳基脲衍生物充当刺猬（Hh）配体，结合并抑制参与同名Hh信号通路的蛋白质。在这篇综述中，我们提供了一些用于合成二芳基脲的方法，并描述了最具代表性的带有二芳基脲部分的抗肿瘤药物，重点关注它们与受体结合的机制和构效关系（SAR）。对这些衍生物的更多了解可能会促使人们寻找新的、更有效的化合物。
