NEUROFARBA Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Florence, Italy.
Department of Pharmacy-Drug Sciences, University of Bari "A. Moro", Bari, Italy.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):974-992. doi: 10.1080/14756366.2020.1747449.
Aiming to deepen the structure-activity relationships of the two P-glycoprotein (P-gp) modulators elacridar and tariquidar, a new series of amide and ester derivatives carrying a 6,7-dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline scaffold linked to different methoxy-substituted aryl moieties were synthesised. The obtained compounds were evaluated for their P-gp interaction profile and selectivity towards the two other ABC transporters, multidrug-resistance-associated protein-1 and breast cancer resistance protein, showing to be very active and selective versus P-gp. Two amide derivatives, displaying the best P-gp activity, were tested in co-administration with the antineoplastic drug doxorubicin in different cancer cell lines, showing a significant sensitising activity towards doxorubicin. The investigation on the chemical stability of the derivatives towards spontaneous or enzymatic hydrolysis, showed that amides are stable in both models while some ester compounds were hydrolysed in human plasma. This study allowed us to identify two chemosensitizers that behave as non-transported substrates and are characterised by different selectivity profiles.
为了深入研究两种 P-糖蛋白（P-gp）调节剂依利达雷和他利奎达的构效关系，我们合成了一系列带有 6,7-二甲氧基-2-苯乙基-1,2,3,4-四氢异喹啉支架的酰胺和酯衍生物，这些衍生物与不同甲氧基取代的芳基部分相连。所得到的化合物被评估了它们对 P-gp 的相互作用特征以及对另外两种 ABC 转运蛋白，多药耐药相关蛋白-1 和乳腺癌耐药蛋白的选择性，结果表明它们对 P-gp 具有非常高的活性和选择性。两种显示最佳 P-gp 活性的酰胺衍生物与抗肿瘤药物阿霉素在不同的癌细胞系中联合给药进行了测试，结果表明它们对阿霉素具有显著的增敏活性。对衍生物在自发或酶促水解条件下的化学稳定性的研究表明，酰胺在两种模型中都很稳定，而一些酯化合物在人血浆中被水解。这项研究使我们能够鉴定出两种作为非转运底物的化疗增敏剂，它们具有不同的选择性特征。
