Takeru Koga, Naoaki Kawahara, Mei Aburada, Asako Ono, Shiori Mae, Aina Yoshida, Yuji Iwaoka, Hideyuki Ito and Akihiro Tai : Antiallergic activity of 3-O-dodecyl-L-ascorbic acid, Molecules, Vol.29, No.1, 69, 2024.
(Summary)
2--Alkyl-l-ascorbic acids and 3--alkyl-l-ascorbic acids were synthesized, and their degranulation inhibitory activities were evaluated. Among ascorbic acid derivatives with butyl, octyl, dodecyl, hexadecyl, and octadecyl groups introduced at the C-2 or C-3 positions, an AA derivative with a dodecyl group introduced at the C-3 position, 3--dodecyl-l-ascorbic acid (compound ), showed the strongest inhibitory activity against antigen-stimulated degranulation. Compound also inhibited calcium ionophore-stimulated degranulation. Compound , in which the hydroxyl group at the C-6 position of compound was substituted with an amino group, and compound , in which the dodecyloxy group at the C-3 position of compound was exchanged with a dodecylamino group, were synthesized, and these derivatives showed weaker inhibitory activity against antigen-stimulated degranulation than that of compound . In addition, orally administered compound inhibited passive cutaneous anaphylaxis reactions in mice with a potency equal to that of oxatomide, an antiallergic agent. These results suggest that compound may be a candidate for antiallergic treatment.
Takeru Koga, Hideyuki Ito, Yuji Iwaoka, Toshiro Noshita and Akihiro Tai : Neurite outgrowth-promoting compounds from the petals of Paeonia lactiflora in PC12 cells, Molecules, Vol.27, No.22, 7670, 2022.
Takeru Koga, Nanako Shiki, Hideyuki Ito, Yuji Iwaoka and Akihiro Tai : Degranulation inhibitors from petals of Coreopsis grandiflora, Records of Natural Products, Vol.16, No.6, 645-650, 2022.
Yuji Iwaoka, Misaki Fukushima, Hideyuki Ito, Takeru Koga, Naoaki Kawahara and Akihiro Tai : Synthesis of ascorbic acid derivatives with different types of C8 straight acyl chain and their neurite outgrowth-enhancing activities, Journal of Nutritional Science and Vitaminology, Vol.68, No.3, 236-239, 2022.
(Summary)
We previously reported that 2-O-α-D-glucopyranosyl-6-O-octanoyl-L-ascorbic acid, having a C straight acyl chain, at a concentration of 100 μM remarkably enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells after being metabolized to L-ascorbic acid (AA) as an active form by esterase and α-glucosidase. In this study, to examine the structure-activity relationship of 6-O-substituted AA derivatives with a C straight acyl chain for neurite outgrowth-promoting activity, we synthesized AA derivatives 1-4 and compared their activities for promoting NGF-induced neurite outgrowth in PC12 cells. AA derivatives 1-4 showed neurite outgrowth-enhancing activity at 100 μM, while AA derivative 2 also showed the enhancing activity at 3 μM. Furthermore, AA derivative 2 as well as AA enhanced NGF-induced neurite outgrowth after being incorporated into PC12 cells via sodium-dependent vitamin C transporter as an anion transporter. The results suggested that AA derivative 2 has neurite outgrowth-enhancing activity in its intact form at a low concentration (3 μM) and that AA derivatives 1-4 showed their activities in the form of AA, a metabolite of these derivatives, at a higher concentration (100 μM).
Takeru Koga and Akihiro Tai : Neurite outgrowth-promoting compounds from cockscomb hydrolysate, Nutrients, Vol.14, No.7, 1422, 2022.
(Summary)
Cockscomb hydrolysate was found to have neurite outgrowth-promoting activity in PC12 cells. To investigate the neurite outgrowth-promoting compounds derived from cockscomb hydrolysate, bioassay-guided purification was carried out. Purified active fractions were obtained by liquid-liquid partition, followed by column chromatography. High-performance liquid chromatography and proton nuclear magnetic resonance analyses of the purified active fractions clarified that the main compounds are threonine, alanine, valine, and methionine. By screening for 20 kinds of amino acids, it was shown that valine and methionine, but not threonine and alanine, have neurite outgrowth-promoting activity. The results of activity evaluation of the mixture of amino acids indicated that alanine enhanced the activity of valine and that the mixture of valine and methionine showed a higher ratio of neurite formation than did each of them alone. On the other hand, dipeptides formed by valine and methionine showed weak neurite outgrowth-promoting activity. A mixture of threonine, alanine, valine, and methionine at the same concentrations as those in cockscomb hydrolysate showed neurite outgrowth-promoting activity comparable to that of cockscomb hydrolysate although threonine, alanine, valine, and methionine alone did not show activity at their concentrations in cockscomb hydrolysate. Therefore, the strong neurite outgrowth-promoting activity of cockscomb hydrolysate was considered to be due to the synergistic effect of threonine, alanine, valine, and methionine.
Toshiro Noshita, Kentaro Fujita, Takeru Koga, Hidekazu Ouchi and Akihiro Tai : Synthesis and biological activity of (±)-7,3',4'-trihydroxyhomoisoflavan and its analogs, Bioorganic & Medicinal Chemistry Letters, Vol.31, 127674, 2021.
(Summary)
Acetylcholinesterase (AChE) inhibitors and neurite outgrowth promoters are thought to alleviate the symptoms of degenerative brain disorders, such as Alzheimer's disease. We designed and synthesized a series of homoisoflavonoids based on the structure of natural homoisoflavan isolated from Dracaena cambodiana dragon's blood. The homoisoflavonoids were then evaluated as AChE inhibitors and neurite outgrowth promoters. The catechol structure of the homoisoflavan B rings was important for AChE inhibition, and some of the homoisoflavonoids significantly promoted neurite outgrowth induced by nerve growth factor (NGF).
Takeru Koga, Takaiku Sakamoto, Eiji Sakuradani and Akihiro Tai : Neurite Outgrowth-Promoting Activity of Compounds in PC12 Cells from Sunflower Seeds, Molecules, Vol.25, No.20, 4748, 2020.
(Summary)
In the current super-aging society, the establishment of methods for prevention and treatment of Alzheimer's disease (AD) is an urgent task. One of the causes of AD is thought to be a decrease in the revel of nerve growth factor (NGF) in the brain. Compounds showing NGF-mimicking activity and NGF-enhancing activity have been examined as possible agents for improving symptoms. In the present study, sunflower seed extract was found to have neurite outgrowth-promoting activity, which is an NGF-enhancing activity, in PC12 cells. To investigate neurite outgrowth-promoting compounds from sunflower seed extract, bioassay-guided purification was carried out. The purified active fraction was obtained by liquid-liquid partition followed by some column chromatographies. Proton nuclear magnetic resonance and gas chromatography-mass spectrometry analyses of the purified active fraction indicated that the fraction was a mixture of β-sitosterol, stigmasterol and campesterol, with β-sitosterol being the main component. Neurite outgrowth-promoting activities of β-sitosterol, stigmasterol, campesterol and cholesterol were evaluated in PC12 cells. β-Sitosterol and stigmasterol showed the strongest activity of the four sterol compounds (β-sitosterol stigmasterol > campesterol > cholesterol), and cholesterol did not show any activity. The results indicated that β-sitosterol was the major component responsible for the neurite outgrowth-promoting activity of sunflower seeds. Results of immunostaining also showed that promotion by β-sitosterol of neurite formation induced by NGF was accompanied by neurofilament expression. β-Sitosterol, which showed NGF-enhancing activity, might be a candidate ingredient in food for prevention of AD.