一系列 N-5 取代的吡咯并[3,2-d]嘧啶类化合物的结构和生物学研究作为潜在的抗癌治疗药物。
Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-]pyrimidines as Potential Anti-Cancer Therapeutics.
机构信息
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
出版信息
Molecules. 2019 Jul 23;24(14):2656. doi: 10.3390/molecules24142656.
Pyrrolo[3,2-]pyrimidines have been studied for many years as potential lead compounds for the development of antiproliferative agents. Much of the focus has been on modifications to the pyrimidine ring, with enzymatic recognition often modulated by C2 and C4 substituents. In contrast, this work focuses on the N5 of the pyrrole ring by means of a series of novel N5-substituted pyrrolo[3,2-]pyrimidines. The compounds were screened against the NCI-60 Human Tumor Cell Line panel, and the results were analyzed using the COMPARE algorithm to elucidate potential mechanisms of action. COMPARE analysis returned strong correlation to known DNA alkylators and groove binders, corroborating the hypothesis that these pyrrolo[3,2-]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC against CCRF-CEM leukemia cells by up to 7-fold, indicating that this position is of interest in the development of antiproliferative lead compounds based on the pyrrolo[3,2-]pyrimidine scaffold.
吡咯并[3,2-d]嘧啶类化合物多年来一直被研究作为开发抗增殖剂的潜在先导化合物。其中大部分研究集中在嘧啶环的修饰上，酶的识别通常通过 C2 和 C4 取代基来调节。相比之下，这项工作通过一系列新型的 N5-取代吡咯并[3,2-d]嘧啶来关注吡咯环的 N5 位。这些化合物针对 NCI-60 人类肿瘤细胞系进行了筛选，并使用 COMPARE 算法对结果进行了分析，以阐明潜在的作用机制。COMPARE 分析与已知的 DNA 烷化剂和沟结合剂具有很强的相关性，这证实了这些吡咯并[3,2-d]嘧啶类化合物作为 DNA 或 RNA 烷化剂的假说。此外，N5 取代使对 CCRF-CEM 白血病细胞的 EC 降低了多达 7 倍，这表明该位置在基于吡咯并[3,2-d]嘧啶骨架的抗增殖先导化合物的开发中具有重要意义。
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