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. 2018 Dec 1;26(22):5962-5972. doi: 10.1016/j.bmc.2018.11.004. Epub 2018 Nov 5.
BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) is a prodrug version of the metal chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide) in which a boronate group prevents metal chelation until reaction with hydrogen peroxide releases SIH, which is then available for sequestering iron(III) and inhibiting iron-catalyzed oxidative damage. While BSIH has shown promise for conditionally targeting iron sequestration in cells under oxidative stress, the yield of SIH is limited by the fact that BSIH exists in cell culture media as an equilibrium mixture with its hydrolysis products isoniazid and 2-formylphenyl boronic acid. In the current study, several BSIH analogs were evaluated for their hydrolytic stability, reaction outcomes with HO, and prochelator-to-chelator conversion efficiency. Notably, the para-methoxy derivative (p-OMe)BSIH ((E)-N'-(5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) and the meta-, para-double substituted (MD)BSIH ((E)-N'-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)methylene)isonicotinohydrazide) showed 1.3- and 1.9-fold improved hydrolytic stability compared to BSIH, respectively, leading to a 22 and 50% increase in chelator released. Moreover, both prochelators were found to protect retinal pigment epithelial cells stressed with either HO or paraquat insult.
BSIH((E)-N'-(2-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯亚甲基)异烟酰基酰肼)是金属螯合剂 SIH((E)-N'-(2-羟基苯亚甲基)异烟酰基酰肼)的前药形式，其中硼酸酯基团阻止金属螯合，直到与过氧化氢反应释放出 SIH，然后可用于螯合铁(III)并抑制铁催化的氧化损伤。虽然 BSIH 已显示出在氧化应激下有条件地靶向细胞中铁螯合的潜力，但 SIH 的产率受到 BSIH 在细胞培养介质中作为其水解产物异烟肼和 2-甲酰基苯硼酸的平衡混合物存在的限制。在本研究中，评估了几种 BSIH 类似物的水解稳定性、与 HO 的反应结果以及前螯合剂-螯合剂转化效率。值得注意的是，对甲氧基衍生物（p-OMe）BSIH((E)-N'-(5-甲氧基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯亚甲基)异烟酰基酰肼)和间、对双取代（MD）BSIH((E)-N'-((6-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊环-2-基)苯并[d][1,3]二恶唑-5-基)亚甲基)异烟酰基酰肼)的水解稳定性分别提高了 1.3 倍和 1.9 倍，导致螯合剂释放增加了 22%和 50%。此外，发现这两种前螯合剂都能保护受到 HO 或百草枯损伤应激的视网膜色素上皮细胞。
