Structure-Activity Relationship of 3-Methylcytidine-5'-α,β-methylenediphosphates as CD73 Inhibitors.

ABSTRACT: We recently reported N⁴-substituted 3-methylcytidine-5'-α,β-methylenediphosphates as CD73 inhibitors, potentially useful in cancer immunotherapy. We now expand the structure-activity relationship of pyrimidine nucleotides as human CD73 inhibitors. 4-Chloro (MRS4598 16; K_i = 0.673 nM) and 4-iodo (MRS4620 18; K_i = 0.436 nM) substitution of the N⁴-benzyloxy group decreased K_i by ∼20-fold. Primary alkylamine derivatives coupled through a p-amido group with a varying methylene chain length (24 and 25) were functionalized congeners, for subsequent conjugation to carrier or reporter moieties. X-ray structures of hCD73 with two inhibitors indicated a ribose ring conformation

SUBMITTER: Scortichini M 

PROVIDER: S-EPMC8865918 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature