摘要
由于近乎完美的与某些受体结合,二芳基脲在构建抗癌分子模型时成为了一个重要的片段/药效团。N基是一个有利的氢键供体,而氧原子恰好是一种优良的受体,随着sorafenib的成功发展,许多新化合物的抗肿瘤活性被合成以及评估。并且,这种结构被用来连接具有高亲和力的DNA烷化剂,此外,二芳基脲在几种激酶抑制剂中存在,如RAF, KDR和极光激酶等,首先,这部分被用于II型抑制剂:它通常形成一个或两个氢键还有一个固定的谷氨酸和一个以DFG为母体的天冬氨酸酰胺骨架。此外,一些二芳基脲衍生物作为Hedgehog(Hh)配体,结合并抑制参与了相同HH信号的通路蛋白。在这篇文章中,我们提供了一些用于二芳基脲合成的方法和描述二芳基脲部分最有代表性的抗肿瘤剂,重点集中在它们的受体机制及构效关系(SAR)。衍生物知识的增加可能会促使我们找到新的和更有效的化合物。
关键词: 二芳基脲;抗癌活性;DNA烷化剂;SAR;DFG-out;激酶抑制剂;杂环化合物。
Current Medicinal Chemistry
Title:Diaryl Urea: A Privileged Structure in Anticancer Agents
Volume: 23 Issue: 15
Author(s): Laura Garuti, Marinella Roberti, Giovanni Bottegoni, Mariarosaria Ferraro
Affiliation:
关键词: 二芳基脲;抗癌活性;DNA烷化剂;SAR;DFG-out;激酶抑制剂;杂环化合物。
摘要: 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.
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Cite this article as:
Laura Garuti, Marinella Roberti, Giovanni Bottegoni, Mariarosaria Ferraro , Diaryl Urea: A Privileged Structure in Anticancer Agents, Current Medicinal Chemistry 2016; 23 (15) . https://dx.doi.org/10.2174/0929867323666160411142532
DOI https://dx.doi.org/10.2174/0929867323666160411142532 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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