Chayah Meriem, Espejo-Román Jose M, Erviti-Marticorena Laura, Huertas-Camarasa Felipe, Domene Carmen, Sánchez-Martín Rosario M, Conejo-García Ana, Cruz-López Olga
Department of Medicinal and Organic Chemistry and Excellence Research Unit of Chemistry Applied to Biomedicine and the Environment, Faculty of Pharmacy, University of Granada, Campus Cartuja s/n 18071 Granada, Spain; GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avda. Ilustración 114 18016 Granada, Spain; Biosanitary Institute of 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, University of Granada, Campus Cartuja s/n 18071 Granada, Spain.
Bioorg Chem. 2025 Mar;156:108212. doi: 10.1016/j.bioorg.2025.108212. Epub 2025 Jan 23.
Molecular interactions at the cell surface, in particular between hyaluronic acid (HA) and the cluster of differentiation 44 (CD44) receptor, are crucial in several biological processes and diseases such as cancer. Thus, inhibition of the HA-CD44 interaction has become a promising therapeutic strategy. Etoposide was the only antitumor compound known to inhibit the binding of CD44 to HA, thereby disrupting key functions that drive malignancy. However, our recent research led to the development of N-alkyl and N-aryl THIQ derivatives, which represented a significant advancement in this field. Here, we further explore the structure-activity relationships of a series of newly designed N-alkylcarbonyl THIQ and study the structural parameters that define both the CD44 inhibitory and antiproliferative activities. Compounds 5d and 7d showed the most improvement of the antiproliferative activity compared to the N-alkylketone 1. Cell viability, competitive binding assays and molecular dynamics studies demonstrated effective inhibition of HA-CD44 binding by compounds 5d and 7d. This work not only expands the arsenal of potential therapeutic agents targeting HA-CD44 interactions but also highlights the potential for new treatments that could more effectively disrupt cancer progression.
细胞表面的分子相互作用，特别是透明质酸（HA）与分化簇44（CD44）受体之间的相互作用，在包括癌症在内的多种生物学过程和疾病中起着关键作用。因此，抑制HA-CD44相互作用已成为一种有前景的治疗策略。依托泊苷是已知的唯一一种能抑制CD44与HA结合的抗肿瘤化合物，从而破坏驱动恶性肿瘤的关键功能。然而，我们最近的研究导致了N-烷基和N-芳基THIQ衍生物的开发，这代表了该领域的重大进展。在此，我们进一步探索了一系列新设计的N-烷基羰基THIQ的构效关系，并研究了定义CD44抑制活性和抗增殖活性的结构参数。与N-烷基酮1相比，化合物5d和7d的抗增殖活性有了最大程度的提高。细胞活力、竞争性结合试验和分子动力学研究表明，化合物5d和7d能有效抑制HA-CD44的结合。这项工作不仅扩大了针对HA-CD44相互作用的潜在治疗药物库，还突出了更有效破坏癌症进展的新治疗方法的潜力。
