Discovery of a Potent Anti-tumor Agent through Regioselective Mono-N-acylation of 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine.
Discovery of a Potent Anti-tumor Agent through Regioselective Mono-N-acylation of 7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine.
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DOI：
10.1039/c3md00134b
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发表时间：
2013-09-01
期刊：
影响因子：
--
通讯作者：
Xiao X
中科院分区：
文献类型：
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作者：
Chen J;Kassenbrock A;Li BX;Xiao X
7H-吡咯并[3，2-f]喹唑啉-1，3-二胺(1)是一种具有重要生物活性的特殊化学支架。然而，目前从1衍生的化学空间是相当有限的。在这里，我们通过开发有效的方法来分别在N1、N3和N7上进行区域选择性单酰化，从而扩展了与1相关的化学空间。利用这种新的方法学，我们制备了一个单-N-酰化吡咯喹唑啉-1，3-二胺的聚焦文库，并对其抗乳腺癌活性进行了筛选。构效关系(SAR)结果表明，N3-酰化化合物的活性普遍高于N1-酰化化合物，而N7-酰化化合物的溶解度显著降低。在所评价的化合物中，7f在MDA-MB-468细胞中的活性是1的8倍。更重要的是，7f对正常人体细胞没有毒性。这些结果表明，7f是一种新的化合物，在不损害正常细胞的情况下，是一种潜在的抗乳腺癌药物。
7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (1) is a privileged chemical scaffold with significant biological activities. However, the currently accessible chemical space derived from 1 is rather limited. Here we expanded the chemical space related to 1 by developing efficient methods for regioselective monoacylation at N1, N3 and N7, respectively. With this novel methodology, a focused library of mono-N-acylated pyrroloquinazoline-1,3-diamines were prepared and screened for anti-breast cancer activity. The structure-activity relationship (SAR) results showed that N3-acylated compounds were in general more potent than N1-acylated compounds while N7-acylation significantly reduced their solubility. Among the compounds evaluated, 7f possessed 8-fold more potent activity than 1 in MDA-MB-468 cells. More importantly, 7f was not toxic to normal human cells. These results suggest that 7f is a novel compound as a potential anti-breast cancer agent without harming normal cells.