Bis-pyranobenzoquinones as a New Family of Reversal Agents of the Multidrug Resistance Phenotype Mediated by P-Glycoprotein in Mammalian Cells and the Protozoan Parasite Leishmania

• Published in: Journal of medicinal chemistry 2008-11, Vol.51 (22), p.7132-7143
• Main Authors: Jiménez-Alonso, Sandra, Pérez-Lomas, Antonio L, Estévez-Braun, Ana, Martinez, Francisco Muñoz, Orellana, Haydee Chávez, Ravelo, Angel G, Gamarro, Francisco, Castanys, Santiago, López, Matías
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Antiparasitic agents; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Benzoquinones - chemical synthesis; Benzoquinones - chemistry; Benzoquinones - pharmacology; Biological and medical sciences; Crystallography, X-Ray; Daunorubicin; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; General aspects; Leishmania tropica - drug effects; Leishmania tropica - genetics; Leishmania tropica - physiology; Medical sciences; Mice; Models, Molecular; Molecular Structure; NIH 3T3 Cells; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Phenotype; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800403b

We have synthesized a set of bis-pyranobenzoquinones through a direct and highly efficient approach based on a double intramolecular domino Knoevenagel hetero Diels−Alder reaction. These bis-pyranobenzoquinone derivatives are compounds whose skeletons have similarities to those of some anticancerous and leishmanicidal drugs. Considering that these drugs are substrates for some members of the ATP-binding cassette (ABC) family of proteins that confers a multidrug resistance (MDR) phenotype, we have carried out the biological evaluation of 20 bis-pyranobenzoquinones as modulators of the MDR phenotype in mammalian cell lines overexpressing P-glycoprotein, MRP1, or BCRP. Moreover, we also tested some of these compounds as potential MDR modulators in a Leishmania tropica line overexpressing a P-glycoprotein-like transporter. Compounds 9 and 10 are, in this work, the most promising reversal agents of MDR in human cancer cell lines, while compounds 4 and 20 showed potent reversal activity of MDR phenotype in the protozoan parasite Leishmania.