4-Substituted-1,2,3-triazolo nucleotide analogues as CD73 inhibitors, their synthesis, in vitro screening, kinetic and in silico studies

Three series of nucleotide analogues were synthesized and evaluated as potential CD73 inhibitors. Nucleobase replacement consisted in connecting the appropriate aromatic or purine residues through a triazole moiety that is generated from 1,3-dipolar cycloaddition. The first related to 4-substituted-1,2,3-triazolo-?-hydroxyphosphonate ribonucleosides. Additional also obtained, which phosphonate group was replaced by bisphosphonate pattern (P–C–P–C, 2) ribose removed leading acyclic derivatives (series 3). ?-hydroxyphosphonylphosphonate ribonucleosides found be potent inhibitors using both purified recombinant protein cell-based assays. Two compounds (2a 2b) contained bis(trifluoromethyl)phenyl naphthyl substituents proved most inhibitors, with IC50 values 4.8 ± 0.8 µM 0.86 0.2 µM, compared standard AOPCP (IC50 value 3.8 0.9 µM), able reverse adenosine-mediated immune suppression on human T cells. This illustrates new type