title: Synthesis and evaluation of effective inhibitors of plant δ1-pyrroline-5-carboxylate reductase.
abstract: Analogues of previously studied phenyl-substituted aminomethylene-bisphosphonic acids were synthesized and evaluated as inhibitors of Arabidopsis thaliana δ(1)-pyrroline-5-carboxylate reductase. With the aim of improving their effectiveness, two main modifications were introduced into the inhibitory scaffold: the aminomethylenebisphosphonic moiety was replaced with a hydroxymethylenebisphosphonic group, and the length of the molecule was increased by replacing the methylene linker with an ethylidene chain. In addition, chlorine atoms in the phenyl ring were replaced with various other substituents. Most of the studied derivatives showed activity in the micromolar to millimolar range, with two of them being more effective than the lead compound, with concentrations inhibiting 50% of enzyme activity as low as 50 μM. Experimental evidence supporting the ability of these inhibitors to interfere with proline synthesis in vivo is also shown.
authors.affiliation: Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy. flg@unife.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Forlani
authors.forename: Lukasz
authors.initials: L
authors.lastname: Berlicki
authors.forename: Mattia
authors.initials: M
authors.lastname: Duò
authors.forename: Gabriela
authors.initials: G
authors.lastname: Dziędzioła
authors.forename: Samuele
authors.initials: S
authors.lastname: Giberti
authors.forename: Michele
authors.initials: M
authors.lastname: Bertazzini
authors.forename: Paweł
authors.initials: P
authors.lastname: Kafarski
mesh_terms: D017360:Arabidopsis / Q000201:enzymology*; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006540:Herbicides / Q000737:chemistry; D010944:Plants / Q000201:enzymology*; D011392:Proline / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011762:Pyrroline Carboxylate Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D006540:Herbicides; D011392:Proline; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase; C487584:aminomethylene-bisphosphonic acid