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

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 foc...

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Autores principales: Cawrse, Brian M., Robinson, Nia’mani M., Lee, Nina C., Wilson, Gerald M., Seley-Radtke, Katherine L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680647/
https://www.ncbi.nlm.nih.gov/pubmed/31340431
http://dx.doi.org/10.3390/molecules24142656
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author Cawrse, Brian M.
Robinson, Nia’mani M.
Lee, Nina C.
Wilson, Gerald M.
Seley-Radtke, Katherine L.
author_facet Cawrse, Brian M.
Robinson, Nia’mani M.
Lee, Nina C.
Wilson, Gerald M.
Seley-Radtke, Katherine L.
author_sort Cawrse, Brian M.
collection PubMed
description 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 EC(50) 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.
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spelling pubmed-66806472019-08-09 Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics Cawrse, Brian M. Robinson, Nia’mani M. Lee, Nina C. Wilson, Gerald M. Seley-Radtke, Katherine L. Molecules Article 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 EC(50) 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. MDPI 2019-07-23 /pmc/articles/PMC6680647/ /pubmed/31340431 http://dx.doi.org/10.3390/molecules24142656 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cawrse, Brian M.
Robinson, Nia’mani M.
Lee, Nina C.
Wilson, Gerald M.
Seley-Radtke, Katherine L.
Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
title Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
title_full Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
title_fullStr Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
title_full_unstemmed Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
title_short Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
title_sort structural and biological investigations for a series of n-5 substituted pyrrolo[3,2-d]pyrimidines as potential anti-cancer therapeutics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680647/
https://www.ncbi.nlm.nih.gov/pubmed/31340431
http://dx.doi.org/10.3390/molecules24142656
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