In silico, spectroscopic, and biological insights on annelated pyrrolo[3,2-e]pyrimidines with antiproliferative activity

The in silico COMPARE analysis was performed on 8-[3-(piperidino)propyl]-4,10-dimethyl-9-phenyl-6-(methylsulfanyl)-3,4-dihydropyrimido[1,2-c]pyrrolo[3,2-e]pyrimidin-2(8H)-one, a compound with promising antiproliferative activity, previously synthetized and screened against a panel of 60 human tumor cell lines. The results evidenced that this compound matches the biological properties of Chromomycin A3 and Actinomycin D, known drugs with high DNA binding affinity. Prompted by such results, a thorough spectroscopic investigation of its DNA aqueous solutions was performed, with the aim to verify its DNA-binding properties. DNA groove-binding interaction was assigned by UV-vis spectrophotometric and circular dichroism (CD) titrations. In agreement with the spectroscopic studies, the test compound has achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Further structure modifications of the tested compound, has led to its analogue, which showed DNA base-pairs intercalating ability. Molecular modeling studies on the annelated pyrrolo[3,2-e]pyrimidines tested were in agreement with the biological evaluation.