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Título
Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum
Autor(es)
Assunto
Instituto de Investigación Biomédica de Salamanca
Ciencias farmacéuticas
Leishmania
Tubulin
DNA-Topoisomerase
Podophyllotoxin
Podophyllic aldehyde
Tubulina
ADN-Topoisomerasa
Podofilotoxina
Aldehído podofílico
Fecha de publicación
2017
Citación
Escudero-Martínez, J. M., Pérez-Pertejo, Y., et al. (2017). Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum. International Journal for Parasitology: Drugs and Drug Resistance, 7(3), 272-285.
Resumen
[EN] Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of
the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and
beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids.
The colchicine binding domain has inspired the discovery and development of several drugs currently in
clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be
selectively targeted by new compounds. This report shows the antileishmanial effect of several series of
compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum
spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania
infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes,
and in mammalian e mouse non-infected splenocytes and liver HepG2 cells e in order to
determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that
the hydroxyl group at position C-7a was a structural requisite to kill the parasites. On regards podophyllic
aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more
potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin
and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction
at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action.
However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.
URI
ISSN
2211-3207
DOI
10.1016/j.ijpddr.2017.06.003
Versión del editor
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