New insights into the mechanism of action of pyrazolo[1,2‐a]benzo[1,2,3,4]tetrazin‐3‐one derivatives endowed with anticancer potential

• Published in: Chemical biology & drug design Vol. 91; no. 2; pp. 463 - 477
• Main Authors: Lauria, Antonino, Mingoia, Francesco, García‐Argáez, Aída Nelly, Delisi, Riccardo, Martorana, Annamaria, Dalla Via, Lisa
• Format: Journal Article
• Language: English
• Published: England 01.02.2018
• Subjects: antiproliferative; DNA‐interacting; intercalation; linear dichroism; molecular docking; pyrazolo[1,2‐a]benzo[1,2,3,4]tetrazin‐3‐one; topoisomerase II; topoisomerase II; DNA-interacting; intercalation; molecular docking; antiproliferative; linear dichroism; pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13108

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‐micromolar 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 to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism 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. 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.