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

• 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
• ISSN: 1420-3049; 1420-3049
• 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.