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

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 foc...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2019-07, Vol.24 (14), p.2656
Main Authors: Cawrse, Brian M, Robinson, Nia'mani M, Lee, Nina C, Wilson, Gerald M, Seley-Radtke, Katherine L
Format: Article
Language:English
Subjects:
Alkylation
anti-cancer
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
antiproliferative
Antiproliferatives
Binders
Biological activity
Cell growth
Cell Line, Tumor
Cell Survival - drug effects
Deoxyribonucleic acid
Dihydrofolate reductase
DNA
DNA alkylator
DNA damage
Drug Screening Assays, Antitumor
Grooves
Humans
Investigations
Kinases
Lead compounds
Leukemia
Lung cancer
Pharmacokinetics
Pyrimidines
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
pyrrolo[3,2-d]pyrimidine
Structure-Activity Relationship
Substitutes
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules24142656