Van Hoof Max, Boon Katrijn, Van Loy Tom, Schols Dominique, Dehaen Wim, De Jonghe Steven
Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium.
KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Box 1043, 3000, Leuven, Belgium.
Eur J Med Chem. 2022 May 5;235:114268. doi: 10.1016/j.ejmech.2022.114268. Epub 2022 Mar 12.
The chemokine receptor CXCR2 and its ligands mediate neutrophil migration to the inflammation site, function as growth factors in many tumor cells and are involved in angiogenesis. Moreover, CXCR2 mediated recruitment of myeloid-derived suppressor cells results in tumor immunosuppression. Consequently, CXCR2 antagonism is a promising strategy for cancer immunotherapy and treatment of inflammatory disorders. Over a decade ago, several thiazolo[4,5-d]pyrimidines were reported as potent CXCR2 antagonists. Optimization of this scaffold focused mainly on the ring substituents, while the aromatic core was mostly unexplored. In this study, a scaffold hopping strategy was applied to the unsubstituted thiazolo moiety. Fourteen novel bicyclic heteroaromatic and cycloaliphatic systems were prepared and evaluated for CXCR2 antagonism using binding and calcium mobilization assays. This study revealed that the triazolo[4,5-d]pyrimidine, the isoxazolo[5,4-d]pyrimidine and the pyrido[3,4-d]pyrimidine scaffolds were endowed with IC values below 1 μM in both assays and therefore are promising skeletons for further optimization.
趋化因子受体CXCR2及其配体介导中性粒细胞向炎症部位迁移，在许多肿瘤细胞中作为生长因子发挥作用，并参与血管生成。此外，CXCR2介导的髓源性抑制细胞募集导致肿瘤免疫抑制。因此，CXCR2拮抗作用是癌症免疫治疗和炎症性疾病治疗的一种有前景的策略。十多年前，有报道称几种噻唑并[4,5-d]嘧啶是有效的CXCR2拮抗剂。该骨架的优化主要集中在环取代基上，而芳香核大多未被探索。在本研究中，一种骨架跃迁策略被应用于未取代的噻唑部分。制备了14种新型双环杂芳族和脂环族体系，并使用结合和钙动员试验评估其对CXCR2的拮抗作用。该研究表明，在两种试验中，三唑并[4,5-d]嘧啶、异恶唑并[5,4-d]嘧啶和吡啶并[3,4-d]嘧啶骨架的IC值均低于1 μM，因此是进一步优化的有前景的骨架。
