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 was 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.

中文翻译：

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通过 7H-吡咯并[3,2-f]喹唑啉-1,3-二胺的区域选择性单-N-酰化发现有效的抗肿瘤剂†

7 H- Pyrrolo[3,2 - f ] quinazoline -1,3-diamine( 1 ) 是一种特殊的化学支架，具有显着的生物活性。然而，目前从1衍生出来的化学空间相当有限。在这里，我们通过开发分别在N ¹、N ³和N ⁷处进行区域选择性单酰化的有效方法，扩展了与1相关的化学空间。使用这种新方法，制备了单-N-酰化吡咯并喹唑啉-1,3-二胺的重点库，并筛选了抗乳腺癌活性。构效关系 (SAR) 结果表明，N ^{3 -}酰化化合物通常比N ^{1 -}酰化化合物而N ^{7 -}酰化显着降低了它们的溶解度。在评估的化合物中，7f在 MDA-MB-468 细胞中具有比1强 8 倍的活性。更重要的是，7f对正常人体细胞没有毒性。这些结果表明，7f是一种新型化合物，可作为潜在的抗乳腺癌药物，不会伤害正常细胞。