Begines Paloma, Sevilla-Horrillo Lucía, Puerta Adrián, Puckett Rebecca, Bayort Samuel, Lagunes Irene, Maya Inés, Padrón José M, López Óscar, Fernández-Bolaños José G
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
Escuela Politécnica Superior, Universidad de Sevilla, Virgen de África 7, E-41011 Seville, Spain.
Pharmaceuticals (Basel). 2020 Oct 31;13(11):358. doi: 10.3390/ph13110358.
Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI = 0.88‒2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14‒32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents.
由于癌症具有多因素性质，它是当今最复杂的疾病之一。尽管到目前为止已开发出大量细胞毒性药物，但并非总能找到良好的治疗方法。近年来，与联合用药相反，多靶点药物在针对多因素疾病方面正受到极大关注。在此，我们完成了酚类衍生物与大量有机硫属元素基序的共轭，旨在开发新型抗增殖剂。分析了它们的抗氧化和抗增殖特性（针对六种肿瘤细胞系和一种非肿瘤细胞系）。此外，为了预测P-糖蛋白介导的化疗耐药性，还进行了P-糖蛋白测定，以确定本文制备的化合物是否可作为该糖蛋白的底物。发现硒衍生物比其硫类似物是更强效的抗增殖剂。此外，连接链的长度和性质以及有机硒支架的性质也被发现是观察到的生物活性的关键特征。具有亚甲二氧基苯基部分和二硒化物官能团的先导化合物表现出良好的活性（GI = 0.88 - 2.0 µM）和对肿瘤细胞系的选择性（选择性指数：14 - 32）；此外，本文考虑的化合物不是P-糖蛋白外排泵的底物，因此避免了来自这种机制的化疗耐药性的产生，而这种耐药性在广泛使用的化疗药物中很常见。
