Topoisomerase IB poisons induce histone H2A phosphorylation as a response to DNA damage in Leishmania infantum.
Int J Parasitol Drugs Drug Resist
; 11: 39-48, 2019 12.
Article
in En
| MEDLINE
| ID: mdl-31563118
DNA topoisomerases are considered consolidated druggable targets against diseases produced by trypanosomatids. Several reports indicated that indenoisoquinolines, a family of non-camptothecinic based topoisomerase poisons, have a strong leishmanicidal effect both in vitro and in vivo in murine models of visceral leishmaniasis. The antileishmanial effect of the indenoisoquinolines implies several mechanisms that include the stabilization of the cleavage complex, histone H2A phosphorylation and DNA fragmentation. A series of 20 compounds with the indenoisoquinoline scaffold and several substituents at positions N6, C3, C8 and C9, were tested both in promastigotes and in intramacrophage splenic amastigotes obtained from an experimental murine infection. The antileishmanial effect of most of these compounds was within the micromolar or submicromolar range. In addition, the introduction of an N atom in the indenoisoquinoline ring (7-azaindenoisoquinolines) produced the highest selectivity index along with strong DNA topoisomerase IB inhibition, histone H2A phosphorylation and DNA-topoisomerase IB complex stabilization. This report shows for the first time the effect of a series of synthetic indenoisoquinolines on histone H2A phosphorylation, which represents a primary signal of double stranded DNA break in genus Leishmania.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Damage
/
Histones
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Leishmania infantum
/
DNA Topoisomerases
/
Cell Cycle Checkpoints
/
Isoquinolines
Limits:
Animals
Language:
En
Journal:
Int J Parasitol Drugs Drug Resist
Year:
2019
Document type:
Article
Affiliation country:
España
Country of publication:
Países Bajos