ABSTRACT
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 series is related to 4-substituted-1,2,3-triazolo-ß-hydroxyphosphonate ribonucleosides. Additional analogues were also obtained, in which the phosphonate group was replaced by a bisphosphonate pattern (P-C-P-C, series 2) or the ribose moiety was removed leading to acyclic derivatives (series 3). The ß-hydroxyphosphonylphosphonate ribonucleosides (series 2) were found to be potent inhibitors of CD73 using both purified recombinant protein and cell-based assays. Two compounds (2a and 2b) that contained a bis(trifluoromethyl)phenyl or a naphthyl substituents proved to be the most potent inhibitors, with IC50 values of 4.8 ± 0.8 µM and 0.86 ± 0.2 µM, compared to the standard AOPCP (IC50 value of 3.8 ± 0.9 µM), and were able to reverse the adenosine-mediated immune suppression on human T cells. This series of compounds illustrates a new type of CD73 inhibitors.
Subject(s)
5'-Nucleotidase/antagonists & inhibitors , Algorithms , Nucleotides/pharmacology , Triazoles/pharmacology , 5'-Nucleotidase/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , GPI-Linked Proteins/antagonists & inhibitors , GPI-Linked Proteins/metabolism , Humans , Kinetics , Molecular Structure , Nucleotides/chemical synthesis , Nucleotides/chemistry , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Two new dimeric monoterpene-linked coumarin glucosides, paratrimerins A (1) and B (2), and three known coumarins, 6-(6-hydroxy-3,7-dimethylocta-2,7-dienyl)-7-hydroxycoumarin (3), ostruthin (4), and ninhvanin (5), were isolated from the roots and stems of Paramignya trimera (OLIV.) GUILL. collected in Khanh Hoa province, Vietnam. Compound 1 comprises two 7-O-ß-D-glucopyranoside coumarins linked at positions 6,6' via a 1,3,4,4-tetrasubstituted cyclohexene containing a monoterpene bridge, whereas compound 2 is a ß-D-apiofuranosyl(1â6)-ß-D-glucopyranosyl derivative of 1. The chemical structures of these compounds were determined by one dimensional (1D) and 2D-NMR and high resolution-electrospray ionization (HR-ESI)-MS spectroscopy.