Structural and Biological Investigations for a Series of N-5 Substituted Pyrrolo[3,2-d]pyrimidines as Potential Anti-Cancer Therapeutics
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AbstractPyrrolo[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. Copyright 2019 by the authors.
SponsorsThe authors thank the National Institutes of Health and NIGMS for financial support through the Chemistry-Biology Interface Program (T32 GM066706, K.L.S.-R. and B.M.C.). N.C.L. was supported by the Nathan Schnaper Intern Program funded in part through NCI grant R25CA186872 to Bret A. Hassel.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85069673602&doi=10.3390%2fmolecules24142656&partnerID=40&md5=61f2b6f8600ce7504690f034a9042234; http://hdl.handle.net/10713/10367