ESR study on the antioxidant activity of TAK-218 in biological model membranes.
TAK-218 has a 2,3-dihydrobenzofuran-5-amine (coumaran) structure which resembles alpha-tocopherol, and is a promising candidate as an agent for central nervous system (CNS) trauma and ischemia. The radical scavenging activity of TAK-218 was studied using electron spin resonance (ESR) spectroscopy. TAK-218 exhibited a more potent scavenging activity towards the hydroxyl radical than did the well-known hydroxyl radical scavengers, mannitol and dimethylsulfoxide. Towards the superoxide radical, TAK-218 showed equal potency to glutathione. TAK-218 reacted rapidly with stable radicals, such as galvinoxyl and 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH), and gave the quinone as a two-electron oxidized product in analogy with alpha-tocopherol. To exhibit an excellent antioxidative activity in living systems, the compounds should not only have the intrinsic radical scavenging activity but also good distribution in the biological lipid-bilayer membrane. To examine the antioxidant activity of TAK-218, the inhibition of lipid peroxidation by alpha-tocopherol and TAK-218 in liposomal membranes was studied using an ESR spin-label technique. Both alpha-tocopherol and TAK-218 completely inhibited lipid peroxidation by radicals generated in an aqueous layer using a water-soluble radical initiator, 2,2'-azobis-(2-amidinopropane) hydrochloride (AAPH). At a high incubation temperature (45 degrees C), alpha-tocopherol scavenged radicals more effectively than TAK-218 on the surface of the membrane, while TAK-218 scavenged radicals more effectively in the interior of the membrane. The difference between TAK-218 and alpha-tocopherol for radical scavenging in the membrane system derives from the different distribution pattern of these compounds. TAK-218 can penetrate the membrane freely and can scavenge the radical in the membrane interior. Furthermore, TAK-218 was shown to inhibit lipid peroxidation initiated by a lipid soluble radical initiator, 2,2'-azobis-(2,4-dimethylvaleronitrile) (AMVN), in a membrane more effectively than alpha-tocopherol.
Murakami
M
M
Discovery Research Laboratories V, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Murakami_Morio@takeda.co.jp
Fukatsu
K
K
Ohkawa
S
S
Kasahara
F
F
Sugawara
T
T
D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008081:Liposomes; D008560:Membrane Fluidity; D008567:Membranes, Artificial
D000975:Antioxidants; D001572:Benzofurans; D016166:Free Radical Scavengers; D008081:Liposomes; D008567:Membranes, Artificial; C104755:TAK 218