Jiménez-Alonso Sandra, Pérez-Lomas Antonio L, Estévez-Braun Ana, Muñoz Martinez Francisco, Chávez Orellana Haydee, Ravelo Angel G, Gamarro Francisco, Castanys Santiago, López Matías
Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, 38206, La Laguna,Tenerife, Spain.
J Med Chem. 2008 Nov 27;51(22):7132-43. 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.
我们通过基于双分子内多米诺Knoevenagel杂环狄尔斯-阿尔德反应的直接且高效的方法合成了一组双吡喃苯醌。这些双吡喃苯醌衍生物的骨架与某些抗癌和抗利什曼原虫药物的骨架相似。鉴于这些药物是赋予多药耐药（MDR）表型的ATP结合盒（ABC）蛋白家族某些成员的底物，我们对20种双吡喃苯醌作为过表达P-糖蛋白、多药耐药相关蛋白1（MRP1）或乳腺癌耐药蛋白（BCRP）的哺乳动物细胞系中MDR表型调节剂进行了生物学评估。此外，我们还在过表达一种P-糖蛋白样转运蛋白的热带利什曼原虫系中测试了其中一些化合物作为潜在的MDR调节剂。在这项工作中，化合物9和10是人类癌细胞系中最有前景的MDR逆转剂，而化合物4和20在原生动物寄生虫利什曼原虫中显示出对MDR表型的强效逆转活性。
