Recognition of GC base pairs of B-DNA by coumarin-based benzimidazopyrimidines

Abstract

A novel series of Fe(III)-catalyzed crescent-shaped coumarin-appended benzo[4,5]imidazo[1,2-a]pyrimidines has been generated using a single-step multi-component approach that includes a coumarin-derived β keto ester, 2-aminobenzimidazole, and various aldehydes. The mild eco-friendly reaction conditions allowed us, for the first time, to construct a library of highly substituted benzo[4,5]imidazo[1,2-a]pyrimidine (CBPy) heterocycles with a wide range of substrate compatibility and excellent yields. This one-pot synthesis is green in nature and conforms to atom economy. The structure of one representative compound (4a) was established by X-ray crystallographic analysis. Our designed CBPys are bent in shape and capable of fitting into the minor groove of the B-DNA structure. Among all the CBPys, compound 4a exhibited the strongest binding interaction (K_d = 2.9 μM) with calf thymus DNA (ctDNA), which is known to form the B-DNA structure under the experimental conditions. A competitive binding study confirmed that the location of 4a was 43.77 Å away from the AT-rich region in the minor groove of B-DNA. It was also established that the crescent shape and the presence of coumarin were crucial for the binding of CBPys with B-DNA structures. Our results with DNA oligonucleotides of variable GC content suggest that compound 4a specifically recognizes and binds to the GC base pairs of the B-DNA structure. Thus, the CBPy class of molecules may open a new avenue for the development of novel therapeutic drugs through GC recognition.