Nonogawa Mitsuru, Arai Toshiyuki, Endo Nobuyuki, Pack Seung Pil, Kodaki Tsutomu, Makino Keisuke
Institute of Advanced Energy, Kyoto University, Gokasyo, Uji, Japan.
Org Biomol Chem. 2006 May 7;4(9):1811-6. doi: 10.1039/b602778d. Epub 2006 Apr 3.
6-Formylpterin (6FP) has been demonstrated to have strong neuroprotective effects against transient ischemia-reperfusion injury in gerbils. Also it has been shown that in rats, 6FP protected retinal neurons even when it was administered after the ischemic insult. Since there is a significant need for such a compound that effectively suppresses the events caused by the lack of oxygen supply, 6FP has attracted further investigation. Unfortunately, however, 6FP is hardly soluble in water at neutral pH and in organic solvents because of its self-assembling ability. Although a several mM solution of 6FP is available in alkaline water, it is unstable. In the present study, a novel chemical derivatization of 6FP has been developed which maintains the formyl group on the 6-position of 6FP, which is essential for the physiological activities of 6FP, and increases solubility in water and organic solvents. In the method, the 2- and 3-positions of 6FP were modified by a three component coupling reaction: 6FP was subjected to the reaction with acid chloride and N,N-dimethylformamide. The derivatives synthesized here, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one 1, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-isobutyrylpteridine-4-one 2, and 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-o-toluoylpteridine-4-one 3, showed high solubility in water (1.0-5.6 mM) and organic solvents. The O(2) conversion property has also been determined for the derivative 1. Using an oxygen electrode, it has been found that O(2) is consumed in the presence of 1 and NADH at around pH 7.4 and that the rate of O(2) consumption is enhanced by UV-A irradiation. Electron paramagnetic resonance (EPR) analysis coupled with DMPO spin trapping has also revealed that in the presence of NADH, 1 converts O(2) to O(2)(-), which is further reduced to OH. By UV-A illumination in the analogous systems, (1)O(2) formation was observed. These results are similar to those reported previously for 6FP.
6-甲酰蝶呤（6FP）已被证明对沙鼠短暂性缺血再灌注损伤具有强大的神经保护作用。此外，研究还表明，在大鼠中，即使在缺血性损伤后给予6FP，它也能保护视网膜神经元。由于迫切需要一种能有效抑制因缺氧引发的一系列事件的化合物，6FP因此吸引了更多的研究。然而，不幸的是，由于其自组装能力，6FP在中性pH值的水中和有机溶剂中几乎不溶。虽然在碱性水中可得到几毫摩尔浓度的6FP溶液，但它不稳定。在本研究中，已开发出一种6FP的新型化学衍生化方法，该方法保留了6FP 6位上的甲酰基（这对6FP的生理活性至关重要），并提高了其在水和有机溶剂中的溶解度。在该方法中，通过三组分偶联反应对6FP的2位和3位进行修饰：使6FP与酰氯和N，N-二甲基甲酰胺反应。在此合成的衍生物，2-（N，N-二甲基氨基亚甲基氨基）-6-甲酰基-3-新戊酰基蝶啶-4-酮1、2-（N，N-二甲基氨基亚甲基氨基）-6-甲酰基-3-异丁酰基蝶啶-4-酮2和2-（N，N-二甲基氨基亚甲基氨基）-6-甲酰基-3-邻甲苯甲酰基蝶啶-4-酮3，在水（1.0 - 5.6 mM）和有机溶剂中显示出高溶解度。还测定了衍生物1的O₂转化特性。使用氧电极发现，在pH约7.4的条件下，在1和NADH存在时O₂会被消耗，并且UV - A照射会提高O₂的消耗速率。电子顺磁共振（EPR）分析结合DMPO自旋捕获还表明，在NADH存在下，1将O₂转化为O₂⁻，O₂⁻进一步被还原为OH。通过在类似体系中的UV - A光照，观察到了¹O₂的形成。这些结果与先前报道的6FP的结果相似。
