Leishmania donovani: a glycosyl dihydropyridine analogue induces apoptosis like cell death via targeting pteridine reductase 1 in promastigotes.
Targeting of pteridine reductase 1 (PTR1) in Leishmania is essential for development of successful antifolate chemotherapy. In search for specific inhibitors of PTR1 we have previously reported phenyl 1,4-dihydropyridine ring as the lead structure showing antileishmanial efficacy in vitro and by the oral route in vivo. In this study, we present programmed cell death inducing potential of this glycosyl dihydropyridine analogue (2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-beta-l-threo-pentofuranos-4-yl)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester). Flow cytometric analysis revealed that this analogue induces cell cycle arrest at G2/M phase with subsequent increase in sub-G1 peak. Incubation of Leishmania promastigotes with this analogue causes exposure of phosphatidylserine to the outer leaflet of plasma membrane, formation of reactive oxygen species, depolarization of mitochondrial membrane potential and concomitant nuclear alterations that included DNA fragmentation. The results from this study on promastigotes give important lead to investigate further in intracellular amastigotes, the biologically relevant parasite stage in host macrophages.
Kaur
Jaspreet
J
Drug Target Discovery & Development Division, Central Drug Research Institute, Chattar Manzil Palace, P.O. Box No. 173, Lucknow 226001, India.
Singh
Biswajit Kumar
BK
Tripathi
Rama Pati
RP
Singh
Prashant
P
Singh
Neeloo
N
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053938:DNA Fragmentation; D016054:DNA, Protozoan / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D005434:Flow Cytometry; D006027:Glycosides / Q000494:pharmacology*; D007893:Leishmania donovani / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000032:analysis
C543591:2,6-dimethyl-4-(3-O-benzyl-1,2-O-isopropylidene-beta-L-threo-pentofuranos-4-y)-1-phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester; D000981:Antiprotozoal Agents; D016054:DNA, Protozoan; D004095:Dihydropyridines; D006027:Glycosides; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; C085592:pteridine reductase