Department of Biochemistry and Molecular Pharmacology, Instituto de Parasitología y Biomedicina López Neyra, CSIC, PTS Granada, Avda. del Conocimiento, 17, Armilla, 18016, Granada, Spain.
Università di Pavia, Dipartimento di Chimica, Viale Taramelli 10, 27100, Pavia, Italy.
Eur J Med Chem. 2022 Mar 15;232:114183. doi: 10.1016/j.ejmech.2022.114183. Epub 2022 Feb 7.
Glycosyl conjugation to drugs is a strategy being used to take advantage of glucose transporters (GLUT) overexpression in cancer cells in comparison with non-cancerous cells. Its extension to the conjugation of drugs to thiosugars tries to exploit their higher biostability when compared to O-glycosides. Here, we have synthesized a series of thiosugar naphthalene diimide conjugates as G-quadruplex ligands and have explored modifications of the amino sidechain comparing dimethyl amino and morpholino groups. Then, we studied their antiproliferative activity in colon cancer cells, and their antiparasitic activity in T. brucei and L. major parasites, together with their ability to bind quadruplexes and their cellular uptake and location. We observed higher toxicity for the sugar-NDI-NMe derivatives than for the sugar-NDI-morph compounds, both in mammalian cells and in parasites. Our experiments indicate that a less efficient binding to quadruplexes and a worse cellular uptake of the carb-NDI-morph derivatives could be the reasons for these differences. We found small variations in cytotoxicity between O-carb-NDIs and S-carb-NDIs, except against non-cancerous human fibroblasts MRC-5, where thiosugar-NDIs tend to be less toxic. This leads to a notable selectivity for β-thiomaltosyl-NDI-NMe12 (9.8 fold), with an IC50 of 0.3 μM against HT-29 cells. Finally, the antiparasitic activity observed for the carb-NDI-NMe derivatives against T. brucei was in the nanomolar range with a good selectivity index in the range of 30- to 69- fold.
糖基化缀合药物是一种利用癌细胞中葡萄糖转运蛋白（GLUT）过表达的策略，与非癌细胞相比。将其扩展到糖基化缀合药物，旨在利用其与 O-糖苷相比更高的生物稳定性。在这里，我们合成了一系列作为 G-四链体配体的硫代糖萘二酰亚胺缀合物，并比较了二甲氨基和吗啉基的氨基侧链修饰。然后，我们研究了它们在结肠癌细胞中的增殖活性，以及它们在 T. brucei 和 L. major 寄生虫中的抗寄生虫活性，以及它们结合四链体的能力及其细胞摄取和定位。我们观察到糖-NDI-NMe 衍生物比糖-NDI-吗啉化合物对哺乳动物细胞和寄生虫的毒性更高。我们的实验表明，糖-NDI-吗啉衍生物与四链体的结合效率较低，细胞摄取能力较差，可能是造成这种差异的原因。我们发现 O-碳-NDIs 和 S-碳-NDIs 之间的细胞毒性差异很小，除了对非癌细胞人成纤维细胞 MRC-5 外，硫代糖-NDIs 的毒性往往较低。这导致β-硫麦芽糖基-NDI-NMe12（9.8 倍）具有显著的选择性，对 HT-29 细胞的 IC50 为 0.3μM。最后，我们观察到碳-NDI-NMe 衍生物对 T. brucei 的抗寄生虫活性在纳摩尔范围内，选择性指数良好，范围在 30 至 69 倍之间。
