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J Med Chem. 2016 Mar 10;59(5):1880-90. doi: 10.1021/acs.jmedchem.5b01429. Epub 2016 Feb 11.

Optimization by Molecular Fine Tuning of Dihydro-β-agarofuran Sesquiterpenoids as Reversers of P-Glycoprotein-Mediated Multidrug Resistance.

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Instituto Universitario de Bio-Orgánica "Antonio González", Departamento de Química Orgánica, and Instituto Canario de Investigación del Cáncer, Universidad de La Laguna , Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife Spain.
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Parque Tecnológico de Ciencias de la Salud , Avenida del Conocimiento s/n, 18016 Armilla, Granada Spain.


P-glycoprotein (P-gp) plays a crucial role in the development of multidrug resistance (MDR), a major obstacle for successful chemotherapy in cancer. Herein, we report on the development of a natural-product-based library of 81 dihydro-β-agarofuran sesquiterpenes (2-82) by optimization of the lead compound 1. The compound library was evaluated for its ability to inhibit P-gp-mediated daunomycin efflux in MDR cells. Selected analogues were further analyzed for their P-gp inhibition constant, intrinsic toxicity, and potency to reverse daunomycin and vinblastine resistances. Analogues 6, 24, 28, 59, and 66 were identified as having higher potency than compound 1 and verapamil, a first-generation P-gp modulator. SAR analysis revealed the size of the aliphatic chains and presence of nitrogen atoms are important structural characteristics to modulate reversal activity. The present study highlights the potential of these analogues as modulators of P-gp mediated MDR in cancer cells.

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