Discovery of a Potent Anti-tumor Agent through Regioselective Mono-N-acylation of 7H-Pyrrolo32-fquinazoline-13-diamine

摘要

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.