In Silico, Spectroscopic, and Biological Insights on Annelated
Pyrrolo[3,2- e]Pyrimidines with Antiproliferative Activity
Author(s):
Antonino Lauria, Alessio Terenzi, Carla
Gentile, Annamaria Martorana, Giuseppe Gennaro, Giampaolo Barone and Anna Maria
Almerico Pages 15 - 26 ( 12 )
Abstract:
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.
Keywords:
Anticancer drugs, DNA interactive drugs,
COMPARE analysis, Annelated pyrrolo-pyrimidines, UV-vis DNA titrations,
Circular Dichroism, Ethidium bromide displacement assay, Cell Cycle.
Affiliation:
Via Archirafi 32, 90123 Palermo – Italy.
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