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

Nia’Mani M Robinson,Nina C Lee,Gerald M Wilson,Brian M Cawrse,Katherine L Seley-Radtke

doi:10.3390/molecules24142656

Abstract

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.

Highlights

Pyrrolo[3,2-d]pyrimidines, or 9-deazapurines, represent a class of compounds that are sterically and electronically similar to the naturally occurring purine nucleobases, with the exception of a hydrogen-bond donating donating moiety moiety at N5 (Figure 1) [1,2,3].hydrogen-bond [1,2,3]
These compounds have seen widespread been extensively utilized in the of small molecule inhibitors of purine biological activity activityand andhave have been extensively utilized in design the design of small molecule inhibitors of nucleoside phosphorylase (PNP) [4,5,6,7,8,9], reductase (DHFR) (DHFR)
The results are presented in terms of growth percent (GP), which is the effect on both activity and selectivity

Summary

Introduction

Hydrogen-bond [1,2,3] These compounds have seen widespread been extensively utilized in the of small molecule inhibitors of purine biological activity activityand andhave have been extensively utilized in design the design of small molecule inhibitors of nucleoside phosphorylase (PNP) [4,5,6,7,8,9], reductase (DHFR) (DHFR). [3], the transient receptor purine nucleoside phosphorylase (PNP)dihydrofolate [4,5,6,7,8,9], dihydrofolate reductase [3], the transient potential channel family [10],family and various kinases [11,12,13]. N5 substitution on the pyrrolo[3,2-d]pyrimidine scaffold, with ten detailed examined the effect of N5 substitution on the pyrrolo[3,2-d]pyrimidine scaffold,novel with compounds synthesized and subsequently tested for antiproliferative activity.

Methods

Results

Conclusion