Dipartimento NEUROFARBA-Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, FI, Italy.
Dipartimento di Scienze della Salute, Università di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy.
Eur J Med Chem. 2014 Nov 24;87:398-412. doi: 10.1016/j.ejmech.2014.09.084. Epub 2014 Sep 30.
As a continuation of our research on potent and efficacious P-gp-dependent multidrug resistance (MDR) reversers, several new N,N-bis(alkanol)amine aryl esters were designed and synthesized, varying the aromatic moieties or the length of the methylenic chain. The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay, where most of the new compounds were shown to be active. In particular the asymmetrical compounds, characterized by two linkers of different length, generally showed fairly high activities as MDR reversers. Some selected compounds (isomers 15-17) were further studied by evaluating their doxorubicin cytotoxicity enhancement (reversal fold, RF) on the K562/DOX cell line. The results of both pharmacological assays indicate that compounds 16 (GDE6) and 17 (GDE19) could be interesting leads for the development of new P-gp dependent MDR modulators.
作为我们对有效且强效的 P-糖蛋白依赖性多药耐药（MDR）逆转剂的研究的延续，我们设计并合成了几种新的 N,N-双（链烷醇）胺芳基酯，改变了芳基部分或亚甲基链的长度。新化合物在阿霉素耐药红白血病 K562 细胞（K562/DOX）的吡柔比星摄取试验中进行了测试，其中大多数新化合物表现出活性。特别是不对称化合物，其特征是两个不同长度的连接子，通常表现出相当高的作为 MDR 逆转剂的活性。一些选定的化合物（异构体 15-17）通过评估它们在 K562/DOX 细胞系上对阿霉素细胞毒性的增强作用（逆转倍数，RF）进一步进行了研究。这两项药理试验的结果表明，化合物 16（GDE6）和 17（GDE19）可能是开发新的 P-糖蛋白依赖性 MDR 调节剂的有前途的先导化合物。
