Diaryl Urea: A Privileged Structure in Anticancer Agents
Diaryl Urea: A Privileged Structure in Anticancer Agents
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DOI：
10.2174/0929867323666160411142532
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发表时间：
2016-01-01
影响因子：
4.1
通讯作者：
Ferraro, Mariarosaria
中科院分区：
文献类型：
--
作者：
Garuti, Laura;Roberti, Marinella;Ferraro, Mariarosaria
二芳基脲由于其与某些受体近乎完美的结合而成为构建抗癌分子的重要片段/药效团。脲NH部分是有利的氢键供体，而脲氧原子被认为是优良的受体。随着索拉非尼的成功开发，许多新的化合物被合成并评价了它们的抗肿瘤活性。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型抑制剂中：它通常与保守的谷氨酸形成一个或两个氢键，并与DFG基序中的天冬氨酸的骨架酰胺形成一个氢键。此外，一些二芳基脲衍生物充当Hedgehog（Hh）配体，结合并抑制参与同型Hh信号传导途径的蛋白质。在这篇综述中，我们提供了一些二芳基脲的合成方法和最具代表性的抗肿瘤药物轴承二芳基脲部分的描述，重点是其机制结合的受体和构效关系（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。
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.