Wang Qin, Franz Katherine J
Duke University, Department of Chemistry, 124 Science Dr., Durham, NC 27708, USA.
Duke University, Department of Chemistry, 124 Science Dr., Durham, NC 27708, USA.
Bioorg Med Chem Lett. 2017 Sep 1;27(17):4165-4170. doi: 10.1016/j.bmcl.2017.07.019. Epub 2017 Jul 8.
The prochelator BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) contains a boronate group that prevents metal coordination until reaction with peroxide releases the iron chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide). BSIH exists in aqueous buffer and cell culture media in equilibrium with its hydrolysis products isoniazid and (2-formylphenyl)boronic acid (FBA). The relative concentrations of these species limit the yield of intact SIH available for targeted iron chelation. While the hydrolysis fragments are nontoxic to retinal pigment epithelial cells, these results suggest that modifications to BSIH that improve its hydrolytic stability yet maintain its low inherent cytotoxicity are desirable for creating more efficient prochelators for protection against cellular oxidative damage.
前螯合剂BSIH（（E）-N'-（2-（4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基）亚苄基）异烟酰肼）含有一个硼酸酯基团，该基团可防止金属配位，直到与过氧化物反应释放出铁螯合剂SIH（（E）-N'-（2-羟基亚苄基）异烟酰肼）。BSIH在水性缓冲液和细胞培养基中与其水解产物异烟肼和（2-甲酰基苯基）硼酸（FBA）处于平衡状态。这些物质的相对浓度限制了可用于靶向铁螯合的完整SIH的产量。虽然水解片段对视网膜色素上皮细胞无毒，但这些结果表明，对BSIH进行修饰以提高其水解稳定性并保持其低固有细胞毒性，对于创建更有效的前螯合剂以防止细胞氧化损伤是可取的。
