Department of Sciences, University of Basilicata, Via dell'Ateneo Lucano 10, Potenza, 85100, Italy.
Department of Chemistry "G. Ciamician", Alma Mater Studiorum-University of Bologna, Via F. Selmi 2, Bologna, 40126, Italy.
Eur J Med Chem. 2019 Feb 15;164:1-7. doi: 10.1016/j.ejmech.2018.12.037. Epub 2018 Dec 17.
With the aim to reduce multidrug resistance several molecules were synthesized and tested for their ability to inhibit ATP-binding cassette (ABC) proteins, which are responsible for drugs transport out from cells. The compound 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one namely 2c, is structurally related to the myocardial-calcium-channel-modulator diltiazem and is considered one of the most efficient P-glycoprotein inhibitors, able to induce apoptosis at low concentrations of doxorubicin in multidrug resistant ovarian cells. In this study experiments were carried out to evaluate other biological activities of compound 2c. We verified the ability of 2c to inhibit ABC transporters do not involved in drug resistance and considering the inhibitory effect of diltiazem on recombinant human carboxylesterase, we observed its inhibitory effect on the esterase activity. Our findings demonstrated that 2c exhibits broad-spectrum activity as ABC transporters inhibitor being able to inhibit ABCC6, a protein belonging to the ABC family although poorly involved in drug resistance. 2c also inhibits cell esterase activity, acetylcholine esterase activity in vitro and cell histone H3 acetylation according to its structural homology with some known HAT inhibitors. The results obtained provide new knowledge on the biological activities of 2c and represent useful information when it is used as an inhibitor of drug resistance.
为了降低多药耐药性，合成了几种分子，并测试了它们抑制三磷酸腺苷结合盒（ABC）蛋白的能力，ABC 蛋白负责将药物从细胞内排出。化合物 8-(4-氯苯基)-5-甲基-8-[(2Z)-戊-2-烯-1-氧基]-8H-[1,2,4]恶二唑[3,4-c][1,4]噻嗪-3-酮，即 2c，与心肌钙通道调节剂地尔硫卓在结构上有关，被认为是最有效的 P 糖蛋白抑制剂之一，能够在多药耐药卵巢细胞中低浓度阿霉素诱导细胞凋亡。在这项研究中，进行了实验以评估化合物 2c 的其他生物学活性。我们验证了 2c 抑制不涉及耐药性的 ABC 转运体的能力，并且考虑到地尔硫卓对重组人羧酸酯酶的抑制作用，我们观察了其对酯酶活性的抑制作用。我们的发现表明，2c 作为 ABC 转运体抑制剂具有广谱活性，能够抑制 ABCC6，一种属于 ABC 家族的蛋白，尽管其在耐药性方面的参与程度较低。2c 还抑制细胞酯酶活性、乙酰胆碱酯酶活性和细胞组蛋白 H3 乙酰化，这与其与一些已知的 HAT 抑制剂的结构同源性有关。所得结果提供了关于 2c 的生物学活性的新知识，并且在将其用作耐药性抑制剂时提供了有用的信息。
