Jatrophane Diterpenes as P-Glycoprotein Inhibitors. First Insights of Structure−Activity Relationships and Discovery of a New, Powerful Lead

2003 ◽  
Vol 46 (15) ◽  
pp. 3395-3402 ◽  
Author(s):  
Gabriella Corea ◽  
Ernesto Fattorusso ◽  
Virginia Lanzotti ◽  
Orazio Taglialatela-Scafati ◽  
Giovanni Appendino ◽  
...  
Keyword(s):  
Structure Activity Relationships ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors

Structure–activity relationships of novel N-acyloxy-1,4-dihydropyridines as P-glycoprotein inhibitors

2007 ◽  
Vol 15 (15) ◽  
pp. 5110-5113 ◽  
Author(s):  
Burkhardt Voigt ◽  
Claudius Coburger ◽  
Joséf Monár ◽  
Andreas Hilgeroth
Keyword(s):  
Structure Activity Relationships ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors

Structure activity-relationships of P-Glycoprotein modulation using a small library of macrocyclic lathyrane diterpenes

Planta Medica ◽  
2012 ◽  
Vol 78 (11) ◽  
Author(s):  
M Reis ◽  
RJ Ferreira ◽  
MMM Santos ◽  
DJVA dos Santos ◽  
J Molnár ◽  
...  
Keyword(s):  
Structure Activity Relationships ◽  
Structure Activity ◽  
P Glycoprotein

scholarly journals Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

2006 ◽  
Vol 50 (9) ◽  
pp. 3102-3110 ◽  
Author(s):  
José M. Pérez-Victoria ◽  
Fernando Cortés-Selva ◽  
Adriana Parodi-Talice ◽  
Boris I. Bavchvarov ◽  
F. Javier Pérez-Victoria ◽  
...  
Keyword(s):  
Active Drug ◽  
Transmembrane Domains ◽  
Drug Efflux ◽  
Binding Domains ◽  
Mammalian Cell Lines ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Leishmania Spp ◽  
Orally Active ◽  
Glycoprotein Inhibitors

ABSTRACT Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-β-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

Flavonoid Dimers as Bivalent Modulators for P-Glycoprotein-Based Multidrug Resistance: Structure-Activity Relationships

ChemMedChem ◽  
2009 ◽  
Vol 4 (4) ◽  
pp. 594-614 ◽  
Author(s):  
Kin-Fai Chan ◽  
Yunzhe Zhao ◽  
Toby W. S. Chow ◽  
Clare S. W. Yan ◽  
Dik Lung Ma ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
P Glycoprotein ◽  
Resistance Structure
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