Chemical Biology and Drug Design
Chemical Biology and Drug Design
3 years ago

New insights on the mechanism of action of Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) endowed with anticancer potential

New insights on the mechanism of action of Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) endowed with anticancer potential
Aída Nelly García-Argáez, Riccardo Delisi, Annamaria Martorana, Lisa Dalla Via, Francesco Mingoia, Antonino Lauria
Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT), has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low micro-molar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations in order to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism (LD) experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, in silico studies have been achieved to better understand the chemical space of the interactions. Interestingly some meaningful structural features, useful for further developments, were found. The 8,9-di-Cl substituted derivative revealed as the most effective in the intercalative process, as well as on the inhibition of catalytic activity of topoisomerase II. Predicted ADME studies confirm that PBTs are promising as potential drug candidates. This article is protected by copyright. All rights reserved. Selected most active PBTs were submitted to further investigations in order to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism (LD), including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, to better understand the chemical space of the interactions, in silico studies have been achieved. Useful insights for future development were found.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13108

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