Synthesis and Evaluation of l-Rhamnose 1C-Phosphonates as Nucleotidylyltransferase Inhibitors

Citations Over TimeTop 18% of 2013 papers

Abstract

We report the synthesis of a series of phosphonates and ketosephosphonates possessing an L-rhamnose scaffold with varying degrees of fluorination. These compounds were evaluated as potential inhibitors of α-D-glucose 1-phosphate thymidylyltransferase (Cps2L), the first enzyme in Streptococcus pneumoniae L-rhamnose biosynthesis, and a novel antibiotic target. Enzyme-substrate and enzyme-inhibitor binding experiments were performed using water-ligand observed binding via gradient spectroscopy (WaterLOGSY) NMR for known sugar nucleotide substrates and selected phosphonate analogues. IC50 values were measured and Ki values were calculated for inhibitors. New insights were gained into the binding promiscuity of enzymes within the prokaryotic L-rhamnose biosynthetic pathway (Cps2L, RmlB-D) and into the mechanism of inhibition for the most potent inhibitor in the series, L-rhamnose 1C-phosphonate.

Related Papers

• → Preparation of a novel series of phosphonate norstatine renin inhibitors(1994)34 cited
• → Synthesis and structures of a pentanuclear Al(iii) phosphonate cage, an In(iii) phosphonate polymer, and coordination compounds of the corresponding phosphonate ester with GaI3 and InCl3(2012)12 cited
• → Facile installation of the phosphonate and (α,α-difluoromethyl)phosphonate functionalities equipped with benzyl protection(1999)37 cited
• → DEALKYLATION OF PHOSPHONATE ESTERS WITH CHLOROTRIMETHYLSILANE(2001)11 cited
• → Effect of the phosphonate group on the reactivity of carbenes. Neighbouring phosphonate group participation(1989)14 cited