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.
J Med Chem. 2016 Mar 10;59(5):1880-90. doi: 10.1021/acs.jmedchem.5b01429. Epub 2016 Feb 11.
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.
P-糖蛋白（P-gp）在多药耐药（MDR）的发展中起着至关重要的作用，这是癌症化疗成功的主要障碍。在此，我们报告了通过优化先导化合物 1 开发了 81 种二氢-β-agarofuran 倍半萜（2-82）的天然产物文库。该化合物文库用于评估其抑制 MDR 细胞中 P-gp 介导的柔红霉素外排的能力。对选定的类似物进行了进一步分析，以确定其对 P-gp 的抑制常数、内在毒性以及逆转柔红霉素和长春新碱耐药性的能力。类似物 6、24、28、59 和 66 的活性比化合物 1 和第一代 P-gp 调节剂维拉帕米更强。SAR 分析表明，脂肪链的大小和氮原子的存在是调节逆转活性的重要结构特征。本研究强调了这些类似物作为 P-gp 介导的癌症细胞 MDR 调节剂的潜力。
