Department of Life Science and Biotechnology, University of Ferrara, Ferrara, Italy.
J Agric Food Chem. 2013 Jul 17;61(28):6792-8. doi: 10.1021/jf401234s. Epub 2013 Jul 3.
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.
合成了先前研究过的苯取代氨甲叉基双膦酸类似物，并将其作为拟南芥 δ(1)-吡咯啉-5-羧酸还原酶抑制剂进行了评估。为了提高它们的效果，在抑制支架中引入了两个主要的修饰：用羟亚甲基双膦酸取代氨甲叉基双膦酸部分，并用亚乙基链取代亚甲基接头来增加分子的长度。此外，苯环上的氯原子被各种其他取代基取代。研究的大多数衍生物在微摩尔至毫摩尔范围内表现出活性，其中两种比先导化合物更有效，其抑制 50%酶活性的浓度低至 50 μM。还展示了支持这些抑制剂在体内干扰脯氨酸合成能力的实验证据。
