- Discovery and structure-activity relationships of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation
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A novel series of spiroindoline derivatives was discovered for use as inducers of oligodendrocyte progenitor cell (OPC) differentiation, resulting from optimization of screening hit 1. Exploration of structure-activity relationships led to compound 18, which showed improved potency (rOPC EC50 = 0.0032 μM). Furthermore, oral administration of compound 18 significantly decreased clinical severity in an experimental autoimmune encephalomyelitis (EAE) model.
- Arai, Yoshikazu,Katayama, Katsushi,Koda, Shuichi,Masumura, Makoto,Murata, Kenji,Muto, Tsuyoshi,Nagata, Tsutomu,Okada, Hiroyuki,Saito, Shoichi,Takashima, Kouhei,Yoshida, Ayako
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- Conformational Switching and the Synthesis of Spiro[2H-indol]-3(1H)-ones by Radical Cyclization
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Radical cyclization of 1-(2-bromophenylamino)cyclohexanecarbonitriles (3, X = CH) and 4-(2-bromophenylamino)-4-piperidinecarbonitriles (3, X = N) provide spiro[2H-indole-2-cyclohexan]-3(1H)-imines (5, X = CH) and spiro[2H-indole-2,4′-piperidin]-3(1H)-imines (5, X = N), respectively, in 33-57% yields. This contradicts a recent report that 1-(2-bromophenylamino)cyclohexane-carbonitrile (3, X-R2 = CH2), treated under apparently identical conditions, led only to nitrile transfer product 6 (X-R2 = CH2). Acidic hydrolyses of the imines provide the corresponding ketones 2 in quantitative yields. Single-crystal X-ray analyses of ketone 2e and nitrile 3e indicate that the relative configuration of the aromatic nitrogen has been inverted during the cyclization. In addition, NOE NMR analyses of spiroindolepiperidine 2c and its aniline-nitrogen-methylated analogue 10a show that the relative conformation of the piperidine ring has inverted. Thus, methylation of 2c acts as a conformational "switch" for the spiroindolepiperidine ring system.
- Sulsky, Richard,Gougoutas, Jack Z.,DiMarco, John,Biller, Scott A.
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p. 5504 - 5510
(2007/10/03)
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