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Open AccessArticle

Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics

1
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA
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Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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Author to whom correspondence should be addressed.
Academic Editor: Christian Ducho
Molecules 2019, 24(14), 2656; https://doi.org/10.3390/molecules24142656
Received: 1 July 2019 / Revised: 20 July 2019 / Accepted: 22 July 2019 / Published: 23 July 2019
(This article belongs to the Special Issue Bioactive Nucleosides and Nucleotides)
Pyrrolo[3,2-d]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-d]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-d]pyrimidines act as DNA or RNA alkylators. In addition, N5 substitution reduced the EC50 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-d]pyrimidine scaffold. View Full-Text
Keywords: pyrrolo[3,2-d]pyrimidine; anti-cancer; antiproliferative; DNA damage; DNA alkylator pyrrolo[3,2-d]pyrimidine; anti-cancer; antiproliferative; DNA damage; DNA alkylator
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MDPI and ACS Style

Cawrse, B.M.; Robinson, N.M.; Lee, N.C.; Wilson, G.M.; Seley-Radtke, K.L. Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics. Molecules 2019, 24, 2656.

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