Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, Granada, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114, 18016, Granada, Spain; Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), SAS-University of Granada, Avenida de Madrid, 15, 18012, Granada, Spain.
Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, Campus Cartuja s/n, 18071, University of Granada, Granada, Spain.
Eur J Med Chem. 2023 Oct 5;258:115570. doi: 10.1016/j.ejmech.2023.115570. Epub 2023 Jun 26.
Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44 cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.
透明质酸（HA）通过与非激酶跨膜糖蛋白 CD44 及其它透明质酸黏附素相互作用，在肿瘤生长和侵袭中发挥关键作用。CD44 在许多实体瘤中表达上调，其与 HA 的相互作用与癌症和血管生成有关。尽管人们努力抑制 HA-CD44 相互作用，但在小分子抑制剂的开发方面进展有限。作为对此项工作的贡献，我们根据现有 CD44 和 HA 的晶体学数据设计并合成了一系列 N-芳基四氢异喹啉衍生物。在这些结构中，发现 2e 具有抗增殖作用，可抑制两种 CD44 癌细胞系的生长，然后合成并评估了两个新类似物（5 和 6）作为 CD44-HA 抑制剂，通过应用计算和基于细胞的 CD44 结合研究。化合物 2-(3,4,5-三甲氧基苄基)-1,2,3,4-四氢异喹啉-5-醇（5）对 MDA-MB-231 细胞的 EC 值为 0.59 μM，有效破坏癌细胞球体的完整性，并以剂量依赖的方式降低 MDA-MB-231 细胞的活力。这些结果表明先导化合物 5 是进一步研究癌症治疗的有前途的候选物。
