As a means of achieving highly sensitive bioluminescence imaging of deep tissues utilizing the firefly luciferin-luciferase (L-L) reaction, we previously reported a luciferin analogue, AkaLumine, which exhibits high cell-permeability and emits near-infrared (NIR) light with high tissue-penetration by the L-L reaction. However, while AkaLumine enables us to observe targets in deep tissues, its poor solubility in aqueous media limits its utility for in vivo imaging. Herein, to address this issue, we have synthesized three AkaLumine derivatives with N-heterocyclic aromatic rings as new red luciferin analogues that have substantially higher solubility than that of AkaLumine in phosphate buffered saline solution. One of the derivatives (herein termed seMpai) exhibits an emission maximum at 675 nm upon L-L reaction with Photinus pyralis luciferase and presents an activity in mouse-tissue imaging similar to that of AkaLumine. It is hoped that seMpai will extend the application of high-sensitivity NIR bioluminescence imaging in a wide range of biomedical research fields.
Aldose reductase (AR) is associated with the onset of diabetic complications. Botryllazine A and its analogues were synthesized and evaluated for human AR inhibitory activity. Analogues possessing aromatic bicyclic systems at the C5 position of the central pyrazine ring exhibited superior AR inhibiting activity relative to the parent botryllazine A. In addition, the benzoyl groups at positions C2 and C3 of the pyrazine ring were dispensable for this improved inhibitory activity. Conversely, a benzoyl group-containing phenolic hydroxyl groups-at either position C2 or C3 of the pyrazine ring was essential for attainment of high inhibitory activity approaching that of sorbinil (a highly effective AR inhibitor).
We synthesized a series of 2-aroyl-4-aryl-1H-imidazoles (2 and 3) and evaluated their in vitro AR inhibitory activity for the first time. We observed improved activities with derivatives having multiple catechol moieties. Diabetes is a metabolic disease characterized by chronic hyperglycemia, which eventually leads to the onset of life-threatening diabetic complications. Aldose reductase (AR) is an enzyme that relates to the onset of diabetic complications, and its inhibition is believed to be effective for preventing or treating diabetic complications. Thus, several AR inhibitors (ARIs) with diverse structures have been developed during the last three decades. 1-6 Most highly potent ARIs are classified into two structural categories: those containing a glycine unit (-NCH2CO2H) and those having a cyclic imide represented by a spirohydantoin or related ring systems. 7-11 These fragments, under physiologic pH conditions, dissociate to form the corresponding conjugate base forms and interact tightly with the active site of AR, which is composed of Tyr48, Lys77, His110, and Trp111, to form hydrogen bonds thus prohibiting the access of glucose to the active site. However, most of them have been omitted from preclinical and clinical trials owing to pharmacokinetic drawbacks, low in vivo efficacy, or adverse side effects. 12 Currently, epalrestat is the only drug approved for clinical use in Japan, China, and India, 13 but it causes side effects such as liver dysfunction. 14 Therefore, the development of new ARIs without these key structures are desired. We have been interested in using the phenolic hydroxyl group as a substitute of the glycine and spirohydantoin units, and have been focusing our interests on pyrazine and imidazole alkaloids isolated from the red ascidian Botryllus leachi (Figure 1). 15,16 The phenolic hydroxyl groups in these compounds are more acidic than phenol itself because electron-withdrawing pyrazine or carbonyl group attaches to the p-position of the hydroxyphenyl group, 17 thereby favoring proton dissociation under physiologic pH
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