TY - JOUR
T1 - SAR Studies of Dihydro-β-agarofuran Sesquiterpenes as Inhibitors of the Multidrug-Resistance Phenotype in a Leishmania tropica Line Overexpressing a P-Glycoprotein-Like Transporter
AU - Cortés-Selva, Fernando
AU - Campillo, Mercedes
AU - Reyes, Carolina P.
AU - Jiménez, Ignacio A.
AU - Castanys, Santiago
AU - Bazzocchi, Isabel L.
AU - Pardo, Leonardo
AU - Gamarro, Francisco
AU - Ravelo, Angel G.
PY - 2004/1/29
Y1 - 2004/1/29
N2 - A series of dihydro-β-agarofuran sesquiterpenes isolated from the leaves of Maytenus cuzcoina (1-10) or semisynthetic derivatives (11-30) have been tested on a multidrug-resistant Leishmania tropica line overexpressing a P-glycoprotein-like transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. Almost all natural compounds showed potent reversal activity with different degrees of selectivity. Compounds 2, 7, and 8 are the most effective reversal agents tested against the multidrug resistance phenotype of Leishmania. Three-dimensional quantitative structure-activity relationships using the comparative molecular similarity indices analysis (CoMSIA) were employed to characterize the steric (contribution of 5.4%), electrostatic (58.9%), lipophilic (10.0%), and hydrogen-bond-donor (13.3%) and -acceptor (7.5%) requirements of these sesquiterpenes as modulators at the P-glycoprotein-like transporter. The most salient features of these requirements are the H-bond interaction between the substituents at the C-2 and C-6 positions with the receptor.
AB - A series of dihydro-β-agarofuran sesquiterpenes isolated from the leaves of Maytenus cuzcoina (1-10) or semisynthetic derivatives (11-30) have been tested on a multidrug-resistant Leishmania tropica line overexpressing a P-glycoprotein-like transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. Almost all natural compounds showed potent reversal activity with different degrees of selectivity. Compounds 2, 7, and 8 are the most effective reversal agents tested against the multidrug resistance phenotype of Leishmania. Three-dimensional quantitative structure-activity relationships using the comparative molecular similarity indices analysis (CoMSIA) were employed to characterize the steric (contribution of 5.4%), electrostatic (58.9%), lipophilic (10.0%), and hydrogen-bond-donor (13.3%) and -acceptor (7.5%) requirements of these sesquiterpenes as modulators at the P-glycoprotein-like transporter. The most salient features of these requirements are the H-bond interaction between the substituents at the C-2 and C-6 positions with the receptor.
U2 - 10.1021/jm0309699
DO - 10.1021/jm0309699
M3 - Article
SN - 0022-2623
VL - 47
SP - 576
EP - 587
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
ER -