Abstract
| Lingua originale | English |
|---|---|
| pagine (da-a) | 463-477 |
| Numero di pagine | 15 |
| Rivista | CHEMICAL BIOLOGY & DRUG DESIGN |
| Volume | 91 |
| Stato di pubblicazione | Published - 2018 |
All Science Journal Classification (ASJC) codes
- Biochemistry
- Organic Chemistry
- Drug Discovery
- Pharmacology
- Molecular Medicine
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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. / Lauria, Antonino; Martorana, Annamaria; Delisi, Riccardo; García-Argáez, Aída Nelly; Mingoia, Francesco; Dalla Via, Lisa.
In: CHEMICAL BIOLOGY & DRUG DESIGN, Vol. 91, 2018, pag. 463-477.Risultato della ricerca: Article
}
TY - JOUR
T1 - 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
AU - Lauria, Antonino
AU - Martorana, Annamaria
AU - Delisi, Riccardo
AU - García-Argáez, Aída Nelly
AU - Mingoia, Francesco
AU - Dalla Via, Lisa
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - antiproliferative; DNA-interacting; intercalation; linear dichroism; molecular docking; pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one; topoisomerase II; Biochemistry; Molecular Medicine
UR - http://hdl.handle.net/10447/295742
UR - http://www.wiley.com/bw/journal.asp?ref=1747-0277
M3 - Article
VL - 91
SP - 463
EP - 477
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
SN - 1747-0277
ER -