Department of Molecular Biology, University of Gdańsk, Kładki 24, Gdańsk, 80-822, Poland.
J Transl Med. 2012 Jul 30;10:153. doi: 10.1186/1479-5876-10-153.
Mucopolysaccharidoses (MPS) are severe metabolic disorders caused by accumulation of undegraded glycosaminoglycans (GAGs) in lysosomes due to defects in certain lysosomal hydrolases. Substrate reduction therapy (SRT) has been proposed as one of potential treatment procedures of MPS. Importantly, small molecules used in such a therapy might potentially cross the blood-brain barrier (BBB) and improve neurological status of patients, as reported for a natural isoflavone, 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4 H-1-benzopyran-4-one, also known as genistein. Although genistein is able to cross BBB to some extent, its delivery to the central nervous system is still relatively poor (below 10% efficiency). Thus, we aimed to develop a set of synthetically modified genistein molecules and characterize physicochemical as well as biological properties of these compounds.
Following parameters were determined for the tested synthetic derivatives of genistein: cytotoxicity, effects on cell proliferation, kinetics of GAG synthesis, effects on epidermal growth factor (EGF) receptor's tyrosine kinase activity, effects on lysosomal storage, potential ability to cross BBB.
We observed that some synthetic derivatives inhibited GAG synthesis similarly to, or more efficiently than, genistein and were able to reduce lysosomal storage in MPS III fibroblasts. The tested compounds were generally of low cytotoxicity and had minor effects on cell proliferation. Moreover, synthetic derivatives of genistein revealed higher lipophilicity (assessed in silico) than the natural isoflavone.
Some compounds tested in this study might be promising candidates for further studies on therapeutic agents in MPS types with neurological symptoms.
黏多糖贮积症（MPS）是由于某些溶酶体水解酶的缺陷导致未降解的糖胺聚糖（GAG）在溶酶体中积累而引起的严重代谢紊乱。底物减少疗法（SRT）已被提议作为 MPS 的潜在治疗程序之一。重要的是，如天然异黄酮 5,7-二羟基-3-(4-羟基苯基)-4H-1-苯并吡喃-4-酮，也称为染料木黄酮，用于此类治疗的小分子可能具有穿过血脑屏障（BBB）并改善患者神经状态的潜力。尽管染料木黄酮在某种程度上能够穿过 BBB，但它向中枢神经系统的输送仍然相对较差（效率低于 10%）。因此，我们旨在开发一组合成修饰的染料木黄酮分子，并表征这些化合物的物理化学和生物学特性。
我们确定了所测试的染料木黄酮合成衍生物的以下参数：细胞毒性、对细胞增殖的影响、GAG 合成动力学、对表皮生长因子（EGF）受体酪氨酸激酶活性的影响、对溶酶体储存的影响、穿过 BBB 的潜在能力。
我们观察到，一些合成衍生物抑制 GAG 合成的效果与染料木黄酮相似，或更有效，并且能够减少 MPS III 成纤维细胞中的溶酶体储存。测试的化合物通常具有低细胞毒性，对细胞增殖的影响较小。此外，染料木黄酮的合成衍生物显示出比天然异黄酮更高的亲脂性（通过计算机评估）。
在这项研究中测试的一些化合物可能是具有神经症状的 MPS 类型治疗剂进一步研究的有希望的候选物。
