Biological evaluation, structure-activity relationships, and three-dimensional quantitative structure-activity relationship studies of dihydro-beta-agarofuran sesquiterpenes as modulators of P-glycoprotein-dependent multidrug resistance.
Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.
Reyes
Carolina P
CP
Instituto Universitario de Bio-OrgAnica Antonio GonzAlez, Universidad de La Laguna and Instituto Canario de Investigación del CAncer, Avenida Astrofísico Francisco SAnchez, 2, 38206 La Laguna, Tenerife, Spain.
Muñoz-Martínez
Francisco
F
Torrecillas
Ivan R
IR
Mendoza
Cristina R
CR
Gamarro
Francisco
F
Bazzocchi
Isabel L
IL
Núñez
Marvin J
MJ
Pardo
Leonardo
L
Castanys
Santiago
S
Campillo
Mercedes
M
Jiménez
Ignacio A
IA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001692:Biological Transport; D029753:Celastraceae / Q000737:chemistry*; D003630:Daunorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D029755:Maytenus / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D018515:Plant Leaves / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013816:Thermodynamics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D005663:Furans; D012717:Sesquiterpenes; D003630:Daunorubicin