Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, CXCR2 antagonist, Scaffold hopping, thiazolo[4,5-d]pyrimidine, 1,2,3-triazolo[4,4-d]pyrimidine, isoxazolo[5,4-d]pyrimidine, pyrido[3,4-d]pyrimidine, CONDENSED PYRIMIDINE SYSTEMS, BIOLOGICAL EVALUATION, DERIVATIVES, CHEMOKINES, INHIBITORS, POTENT, 1,2,3-triazolo[4,5-d]pyrimidine, Cell Movement, Pyrimidines, Receptors, Interleukin-8B, Structure-Activity Relationship, C14/19/078#55221580, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

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 IC50 values below 1 μM in both assays and therefore are promising skeletons for further optimization.