PDF(Pubmed)
Abstract：
Induction of fetal hemoglobin (HbF) is highly beneficial for patients carrying β-thalassemia, and novel HbF inducers are highly needed. Here, we describe a new class of promising HbF inducers characterized by an isoxazole chemical skeleton and obtained through modification of two natural molecules, geldanamycin and radicicol. After preliminary biological assays based on benzidine staining and RT-qPCR conducted on human erythroleukemic K562 cells, we employed erythroid precursors cells (ErPCs) isolated from β-thalassemic patients. ErPCs weretreated with appropriate concentrations of isoxazole derivatives. The accumulation of globin mRNAs was studied by RT-qPCR, and hemoglobin production by HPLC. We demonstrated the high efficacy of isozaxoles in inducing HbF. Most of these derivatives displayed an activity similar to that observed using known HbF inducers, such as hydroxyurea (HU) or rapamycin; some of the analyzed compounds were able to induce HbF with more efficiency than HU. All the compounds were active in reducing the excess of free α-globin in treated ErPCs. All the compounds displayed a lack of genotoxicity. These novel isoxazoles deserve further pre-clinical study aimed at verifying whether they are suitable for the development of therapeutic protocols for β-thalassemia.
摘要：
胎儿血红蛋白（HbF）的诱导对携带β-地中海贫血的患者非常有益，和新的HbF诱导物是高度需要的。这里,我们描述了一类新的有前途的HbF诱导剂，其特征是异恶唑化学骨架，并通过修饰两个天然分子获得，格尔德霉素和雷尼考.在人红白血病K562细胞上进行的基于联苯胺染色和RT-qPCR的初步生物学测定后，我们采用分离自β-地中海贫血患者的红系前体细胞(ErPCs)。用适当浓度的异恶唑衍生物处理ErPCs。通过RT-qPCR研究了珠蛋白mRNA的积累，和高效液相色谱法生产血红蛋白。我们证明了异唑在诱导HbF中的高功效。这些衍生物中的大多数表现出类似于使用已知的HbF诱导剂观察到的活性，例如羟基脲(HU)或雷帕霉素;一些分析的化合物能够以比HU更有效地诱导HbF。所有化合物在减少经处理的ErPC中过量的游离α-珠蛋白方面具有活性。所有化合物均显示缺乏遗传毒性。这些新型异恶唑值得进一步的临床前研究，旨在验证它们是否适合开发β-地中海贫血的治疗方案。
